KR100245955B1 - Tricyclic antipsychotic compounds - Google Patents

Abstract

Compounds of formula I, and pharmaceutically acceptable salts thereof, useful in the treatment of neuropsychiatric disorders such as psychoses; pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier; and methods of treating neuropschiatric disorders comprising administering to a mammal (including man) in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. <IMAGE>

Description

Metanoanthracene compounds

The present invention relates to metanoanthracene compounds. These compounds have been found to be useful as antagonists to dopamine at the D ₂ receptor. Since the compounds exhibit antidopaminergic activity, they are useful as antipsychotics and neuroleptics to alleviate neuropsychiatric disorders such as psychosis. In addition, as a D ₂ antagonist, the compounds according to the invention are useful for treating other disorders associated with dopamine activity, such as gastrointestinal disorders, emesis and dyskinesia.

According to the present invention there is provided a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

Wherein X and Y are each selected from hydrogen, halo and (1-6C) alkoxy, and R^OneSilver (A) (1-6C) alkyl, (B) (1-6C) alkyl, (1-6C) alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl , General formula SO₂NR^aR^bAminosulfonyl and the general formula CONR^cR^dAminocarbonyl represented by^a, R^b, R^cAnd R^dAre each selected from hydrogen, 2-pyrrolidinyl and (1-6C) alkyl, or R^aAnd R^b, And R^cAnd R^dIs Together with the nitrogen atom to which they are each bonded form a 5- or 6-membered heterocyclic ring in which said nitrogen atom is the only hetero atom) and R^hRⁱN (1-3C) alkyl, where R^hAnd RⁱIs phenyl and naphthyl which may each have 0 to 3 substituents selected from the group consisting of hydrogen and (1-3C) alkyl, (C) phenyl (1-3C) alkyl and naphthyl (1-3C) Alkyl (wherein phenyl and naphthyl groups may have 0 to 3 substituents selected from the meanings of the phenyl and naphthyl substituents described in (B) above), (D) 1 to 3 heterologous selected from nitrogen, oxygen and sulfur (1-6C) alkoxy, (1-6C) alkoxycarbonyl, (1-6C) hydroxyalkyl, benzyloxy containing atoms and may have (1-6C) alkyl, hydroxy, trifluoromethyl groups , Halo, (1-3C) alkylaminocarbonyl (1-3C) alkyl, aminocarbonyl as described in (B) above, R^eS (0) n, R^fNH and R^g5- and 6-membered heteroaryl rings, or benz derivatives thereof, which may have 0 to 2 substituents selected from S, wherein R^eAnd R^fAre each selected from hydrogen and (1-6C) alkyl, n is 0, 1 or 2, and R is^gIs selected from (1-3C) alkylcarbonylaminophenyl and di (1-3C) alkylamino (1-6C) alkyl). (E) heteroaryl, wherein the heteroaryl moiety is a 5 or 6 membered ring as described in (D) above and may have 0 to 2 substituents selected from the meaning of the heteroaryl substituent described in (D) above ( 1-3C) alkyl.

The present invention also provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable diluent or carrier.

In addition, the present invention consists in administering an effective amount of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, to a mammal, including a human, in need of treatment for a neuropsychiatric disorder. It provides a method for treating.

As used herein, the terms "alkyl" and "alkoxy" include both straight and branched chain radicals, but when describing individual radicals such as "propyl" or "propoxy" it is only straight chain ("normal, normal It is to be understood that ") means only radicals and that branched chain isomers such as" Asopropyl "or" isopropoxy "are specified specifically.

As used herein, the term "halo" refers to fluoro, chloro, boromo and iodine unless otherwise noted.

Since the compound of formula (I) may contain asymmetrically substituted carbon and / or sulfur atoms, they may exist in optically active and racemic forms and may be separated. Some compounds exhibit polymorphism. It is to be understood that the present invention encompasses any racemic form, optically active form, isomorphic form or stereoisomeric form, or mixtures thereof having properties useful for the treatment of psychosis, and how to prepare compounds of the optically active form. (E.g., by decomposing racemate forms by recrystallization techniques, synthesizing from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) and the standard tests described below. Methods for measuring the efficacy of the treatment of psychosis by means of the art are well known in the art.

Specific meanings of (1-6C) alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.

Specific meanings of (1-3C) alkyl include methyl, ethyl and propyl.

Specific meaning of (1-6C) alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy , Hexoxy and isohexoxy.

Specific meanings of (1-3C) alkoxy include methoxy, ethoxy and propoxy.

Specific meanings of 5- and 6-membered heteroaryl rings containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyramidinyl, 4-pyrimidinyl, 3-pyrazinyl, 4-pyridazinyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxyzolyl, 4-oxazolyl , 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-oxadiazolyl, 5-oxadiazolyl, 2-furyl, 3-furyl, 2-imidazolyl, 4-imi Dazolyl, 5-imidazolyl, 2-thienyl and 3-thienyl. The ring may optionally have substituents as described above.

Specific meanings of the benz derivatives of 5- and 6-membered heteroaryl groups include various quinolinyl, isoquinolinyl and benzothiazolyl groups which may be substituted as described above.

The specific meaning of (1-6C) hydroxyalkyl is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy Hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl and 3-hydroxybutyl.

More specific meanings of X and Y include hydrogen and halo.

More specific meanings of (1-6C) alkyl include (1-3C) alkyl including methyl, ethyl, propyl, isopropyl and t-butyl.

More specific meanings of (1-6C) alkoxy include (1-3C) alkoxy, including methoxy, ethoxy, propoxy and isopropoxy.

More specific meanings of 5- and 6-membered heteroaryl rings containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur include 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isothiazolyl , 4-isothiazolyl, 5-isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl and 4-imidazolyl, the ring optionally being described above. As substituted.

More specific meanings of the benz derivatives of 5- and 6-membered heteroaryl groups include 3-quinolyl, 4-isoquinolinyl, 2-methoxy-3-quinolyl, 2-benzothiazolyl, 6-methoxy- 2-benzothiazolyl and 2-benzthienyl.

More specific meanings of (1-6C) hydroxyalkyl include (hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl); 1-3C) hydroxyalkyl.

X and Y are preferably hydrogen and chloro.

When R ¹ is (1-6C) alkyl, it is preferred that it is t-butyl (also referred to herein as a 1,1-dimethylethyl group).

When R ¹ is phenyl and naphthyl substituted with 0 to 3 substituents, 2-methoxyphenyl, 3-methoxyphenyl and the general formula R ^a R ^b NSO ₂ , wherein R ^a and R ^b are each hydrogen, Preference is given to phenyl substituted in the 2 or 3 position by aminosulfonyl, which is selected from methyl and ethyl.

When R ¹ is a 5-membered heteroaryl ring substituted by 0 to 2 substituents, preference is given to thienyl and furyl.

When R ¹ is a 6-membered heteroaryl ring substituted by 0-2 substituents, it is substituted at position 2 with (1-6C) alkylthio, (1-6C) alkylsulfonyl, or (1-6C) alkoxy Or unsubstituted 3-pyridyl.

The compound represented by the following general formula (I) is preferable.

X and Y are each selected from hydrogen and chloro, and R ¹ is (i) t-butyl, (ii) 2-methoxyphenyl, 3-methoxyphenyl and the general formula R ^a R ^b NSO ₂ , wherein R ^a And R ^b are selected from hydrogen, methyl and ethyl, respectively, and are substituted at the 2- or 3-position by aminosulfonyl, and (iii) thienyl, furyl and 2-position (1-6C) alkoxy, (1-6C) alkylthio, or 3-pyridyl optionally substituted with (1-6C) alkylsulfinyl.

Specifically preferred compounds are as follows.

1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9-yl-methyl) -4- (1,1-dimethylethyl) piperidine-4 -Ol, 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylsulfinyl-3-pyridyl) piperidin-4-ol, 1 -(9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylthio-3-paradil) piperidin-4-ol and 1- (2-chloro -9,10-dihydro-9,10-methanoanthracene-9-yl-methyl) -4- (2-methoxy-3-pyridyl) piperidin-4-ol.

In general, 9S, 10S stereochemistry is preferred when X is chloro and Y is hydrogen. In this case, the stereochemistry can be determined by combining an acid chloride of formula (III) (G = chloro) with a chiral compound, such as oxazolidinone of formula (IV), to form two diastereomers. have.

After separation and recrystallization of the diastereoisomers, the structure is determined by X-rays to provide absolute stereochemistry at 9 and 10 positions.

The compounds of formula (I) may be prepared by methods including those known in the chemical art for the preparation of structurally similar compounds. The method for preparing the amide of general formula (I) described above and the chemical intermediates included in the method constitute another feature of the present invention, which method follows the following procedure. Hereinafter, unless otherwise stated, the meaning of the generic radicals is as defined above. This manufacturing method can generally be performed as follows (a)-(d).

(a) A method of treating a piperidone represented by the following general formula (II) with a corresponding compound represented by the general formula R ¹ Li in an aprotic solvent such as THF, wherein the lithium compound is represented by the general formula R ¹ Z ( Wherein Z is a halo group or, optionally, hydrogen) in situ by reacting a (1-6C) alkyl lithium compound, for example n-butyl lithium, under a temperature of typically -20 ° C to -100 ° C. Easy to prepare in a solid phase], (b) a process for treating a corresponding amide of formula (IIa) with a suitable reducing agent such as lithium aluminum hydride or borane dimethylsulfide complex, (c) The aldehyde of III) (G is hydrogen) is treated with the corresponding piperidine of the general formula (IV) in the presence of a reducing agent, for example sodium cyanoborohydride, or (d) in X and Y General formula wherein either is (1-6C) alkoxy ( If a compound of I) is to be prepared, the corresponding compound of formula (I) wherein X or Y is hydroxy is converted to the corresponding (1-6C) alkyl halide in the presence of a base (e.g., alkali metal hydride) Method of Treatment (This reaction can be carried out at a temperature of 0 ° C. to room temperature in a suitable solvent such as THF, and the method of preparing the hydroxy precursor is described in Examples 89-91 below):

If commercially available products are not available, the starting materials required for the treatment procedures as described above may be prepared using standard organic chemistry techniques, techniques similar to the methods of synthesizing structurally similar known compounds, techniques similar to those described above, or the following examples. It can manufacture by the method selected from the processing procedures described in the following. Compounds represented by the general formula R ¹ Z can be prepared by techniques described in or similar to those described in Brandsma et al., Preparative Polar Organometallic Chemistry I, Springer-Verlag, lst edition, 1987. The following standard chemical abbreviations and acronyms were used in the following descriptions and reaction schemes. "Et" ethyl, "THF" tetrahydrofuran, "t-Bu t-butyl", "RT" room temperature, "DMSO" dimethylsulfoxide, "Me" methyl, "Cbz" carbenzyloxy and "Ph" phenyl . When referring to a Grignard reagent or an alkyl lithium compound, "Z" means a halo group such as chloro.

Common intermediates in the preparation of the compounds according to the invention are the acids of the general formula (III) (G is hydroxyl) or acid halides (G is a halo such as chloro). It can be prepared as shown.

Scheme I

The anthraquinone of the general formula (10) can be reduced to the anthracene of the general formula (12) using zinc and aqueous ammonia. Anthracene 12 can then be converted to the corresponding 9-aldehyde 14 using phosphorus oxytrichloride and N-methylformanilide. The reaction of aldehyde 14 with vinyl acetate (Diels-Alder reaction) yields compound 16 bridged, followed by conversion to the corresponding acid 18 using chromium trioxide (in the presence of sulfuric acid). Acid 18 is subsequently treated with thionyl chloride (for example in toluene) to form the corresponding 9-acid chloride, followed by sodium azide (for example in a water / acetone mixture) to give the corresponding 9-acyl aza A hydroxyl group by decomposing an aldehyde group, followed by heating (for example, heating in toluene), followed by a displacement reaction to form a corresponding isocyanate, followed by treatment with an alkali metal hydroxide (for example in an alcohol such as ethanol) to decompose the acetyl group. And 9-amine 20 can be obtained by hydrolysis of the isocyanate to form amino groups. Amine 20 can be obtained by treating the amine 20 with an alkali metal (eg sodium) nitrite (eg in acetic acid) to shrink the ring to obtain the 9-aldehyde of formula 22. By oxidizing aldehyde 22 with chromium trioxide in the presence of sulfuric acid, the rising 9-acid of formula 24 (9-acid, G = hydroxyl, corresponding to the acid of formula (III)) can be obtained. The corresponding 9-acid chloride can be obtained by treating acid 24 with thionyl chloride or oxalyl chloride.

If one wants to prepare a metanoanthracene substituted with 2,7-dihal, the (undigested) acid mono-substituted by a given halo (eg chloro) substituent at the 2 position, as described in the Examples below, Although 24 may be prepared as a starting material, optically concentrated isomers (26, etc.) may be used when preparing a product substituted with optically concentrated dihal in the following description. The lower 9-alkyl ester can be prepared by reacting acid 24 with thionyl chloride to make the corresponding 9-acid chloride followed by addition of lower alcohols (eg methanol or ethanol). The 2-halo ester can then be nitrated at position 7 by reacting with a suitable nitration agent such as a complex of trifluoroacetic anhydride and ammonium nitrate under an inert gas (eg nitrogen) atmosphere. The reaction generally provides a mixture of 2-halo-6-nitro and 2-halo-7-nitro positional isomers which can be separated by conventional separation techniques such as recrystallization or flash chromatography on silica gel. Can be. The 2-halo-7-nitro isomer can be reduced to the corresponding 7-amino-2-halo compound by a suitable reducing agent such as stannous chloride, and the resulting 7-amino-2-halide is t-butyl The reaction can be converted to the corresponding 2,7-dihalo alkyl esters by reaction with a deazolation agent such as nitrite followed by treatment with a copper (II) halide such as copper (II) chloride or copper (II) bromide. The ester can then be decomposed using a suitable base such as an alkali metal hydroxide to give the acid substituted with the corresponding 2,7-dihal.

In addition, in the case of preparing a metanoanthracene (for example, 2-chloro-7-methoxy derivative) having an oxygen-containing substituent, as described in Examples below, 7-amino-2 as described above A halo derivative can be prepared as starting material. The amine was treated with a deazolation agent such as t-butyl nitrite followed by a salt of a suitable acid such as trifluoroacetic acid (for example a salt formed by potassium carbonate in the solvent trifluoroacetic acid). The trifluoroacetate formed is hydrolyzed by conventional means and treated with a base in the presence of the corresponding (1-6C) alkyl halide (e.g. methyl iodide) to the (1-6C) alkyl group at the oxygen atom. Can be combined.

As represented by R and S in Scheme I, acid 24 is a racemate. Racemic acid 24 can be resolved by fractional crystallization of diastereomeric salts, prepared by addition of chiral amines such as (+)-pseudoephedrine, from an appropriate solvent such as ethanol to produce an optically concentrated acid 26. Acid 26 is treated with thionyl chloride to yield the corresponding optically concentrated acid chloride. Optically concentrated intermediates can be used in chiral synthesis to prepare optically concentrated compounds according to the invention.

The amide of formula (IIa) may be prepared by reducing the acid chloride of formula (III) (G is chloro) in the presence of a base such as trialkylamine, for example triethylamine, It can be prepared by treatment with ferridine.

As the piperidine of formula (II) is shown in Scheme II, the corresponding hydroxypiperidine of formula 32 is used with chromium trioxide in the presence of a suitable oxidizing agent, for example (1) sulfuric acid Suitable solvents such as acetone or (2) sulfur trioxide-pyridine complexes in the presence of a base such as trialkylamine (specifically triethylamine) and a mixture of methylene chloride and DMSO Or (3) by oxidizing with oxalyl chloride and DMSO followed by a base such as trialkylamine and using a solvent such as methylene chloride.

Scheme II

In addition, the hydroxypiperidine of Formula 32 can be prepared by either of the two routes shown in Scheme II above. Treatment of 9-aldehyde 22 directly with 4-hydroxypiperidine, followed by reduction (in the presence of a desiccant such as molecular sieve) with sodium cyanoborohydride in a suitable solvent such as methineol to hydroxy piperi Dean 32 can be prepared.

Alternatively, 9-aldehyde 22 is first oxidized and then converted to the corresponding 9-acid chloride as described above, followed by treatment with excess 4-hydroxypiperidine or trialkylamine (eg triethyl Treatment with addition of a base such as amine) yields the corresponding amide 30. Hydroxy piperidine 32 can then be prepared by reducing amide 30 with diethyl ether or with lithium aluminum hydride in tetrahydrofuran.

Piperidine represented by the general formula (IV) can be synthesized as shown in Scheme III.

Scheme III

By reacting 4-hydroxypiperidine 50 with carbobenzyloxy chloride (Cbz-C1) in the presence of a base such as Et ₃ N to protect the piperidino nitrogen atom, the corresponding 1- (carbenzyloxy) Piperidin-4-ol 52 is obtained. Piperidin-4-ol 52 is oxidized using oxalylchloride and DMSO followed by treatment with base (Et ₃ N) in a solvent such as methylene chloride to give the corresponding protected 4-piperidone 54. Piperidone 54 is treated with an organolithium compound R ¹ Li or Grignard reagent R ¹ MgZ in a solvent such as THF or Et ₂ O at a temperature between -20 ° C. and -70 ° C. to give the corresponding protected hydroxypiperi Dean gets 56 The protected hydroxypiperidine 56 was deprotected in a solvent such as ethanol using a palladium / carbon catalyst (eg 10% Pd / C) to give hydroxypiperidine of the general formula (IV) You can get it.

Many of the starting materials for the aforementioned synthetic methods are commercially available and / or described in the scientific literature.

Examples of suitable pharmaceutically acceptable salts include, for example, physiologically acceptable anions such as tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, α-ketoglutarate and It is an organic acid addition salt formed by an acid that provides α-glycerophosphate. Suitable inorganic salts such as sulfates, nitrates and hydrochlorides can also be formed. Pharmaceutically acceptable salts can be prepared using standard methods known in the art, for example, by reacting a compound of Formula (I) with an acid that provides a physiologically acceptable anion.

When used to treat psychosis, the compound of formula (I) is typically administered as a pharmaceutical composition consisting of the compound of formula (I) as defined above and a pharmaceutically acceptable excipient or carrier and suitable for the particular route of administration chosen. . Such compositions constitute another feature of the present invention. Such weak compositions can be prepared using conventional methods and excipients and binders, and can exist in a variety of dosage forms. For example, the compositions may be in the form of tablets, capsules, solutions or suspensions for oral administration, suppositories for rectal administration, sterile solutions or suspensions for intravenous, subcutaneous or intramuscular injection or infusion, or patches for transdermal administration. have. Oral administration is preferred.

The dosage of the compound of formula (I) to be administered, as well as the route of administration, the severity of psychotic symptoms and the size and age of the patient will depend upon the principles known in the art. Typically, the compound of formula (I) is administered to a warm-blooded animal (eg a human) in an effective amount, generally from a dose of about 0.01 mg / kg body weight to about 40 mg / kg body weight daily. For example, when the compound is administered intramuscularly, it is administered at a dose of about 0.01 mg / kg body weight to about 10 mg / kg body weight. When administered orally, the compound is administered at a dose of about 0.1 mg / kg body weight to 40 mg / kg body weight.

Those skilled in the art will appreciate that the compounds of formula (I) may be co-administered with other therapeutic or prophylactic agents and / or with agents that are medically compatible with the compounds of formula (I). In general, compounds belonging to the scope of the present invention showed no signs of significant toxicity in experimental test animals when using multiple doses of the lowest effective dose.

Since the compounds of the general formula (I) are antagonists of the dopamine D-2 receptor, they are considered to be useful as antipsychotics. D-2 antagonism may be associated with antagonism of [ ³ H] -sphyrone binding (test A) and / or antagonism of apomorphine-induced climbing and interference with apomorphine-induced swimming (test B). Prove by the same standard test.

[Test A]

Receptor binding assays used to determine the affinity of various compounds for the dopamine (DA) D-2 receptor subtype are described by Saller & Salama, J. Pharmacol Exp. Ther. 236, p714, 1986.

Specifically, rat striatum membranes were used. Tissue membranes were prepared and washed once with a 50-fold volume of a suitable Tris HCl buffer solution. For D-2 receptor binding assays, progenitor membranes were suspended in 50 mM Tris HCl containing 40 nM ketanserine at pH 7.7 until the final concentration was 8 mg / mL. Nonspecific binding to the D-2 receptor was measured in the presence of 1.0 μM of (+)-butaclamole. At least five concentrations of each drug were used in triplicate to determine the IC ₅₀ (drug concentration causing 50% substitution) for the substitution of 0.5 nM [ ³ H] spirferon. 1/2 mL of the membrane suspension was incubated with the compound or excipient under investigation or a nonspecific drug, ligand and a suitable Tris HCl buffer solution. For each tube, the combined final reactant volume was 1 mL to incubate at 37 ° C. for 15 minutes to facilitate binding and equilibrate. The Branded filtration system with a GF / B filter was used to separate the bound drug from the free drug. The amount of drug bound to the membrane was analyzed using the liquid scintillation counting technique. IC ₅₀ values were obtained through least squares regression of the data logit-log transformation. Representative IC ₅₀ values were 3 nM (nano water) for the compound of Example 49 and 12 nM for the compound of Example 5.

[Test B]

Female Swiss-Webster mice weighing about 20 g were fasted for 24 hours before oral administration of various doses of excipients or various doses of test treatment (N = 20 mice / treatment group). After 30 minutes, mice were subcutaneously administered apomorphine HCl 1.25 mg / kg and placed in climbing cages. The climbing cage is 9 cm wide, 15 cm deep, and 30 cm high. On one wall there are 27 horizontal rungs 1 cm apart. Thirty minutes after apomorphine administration, each mouse was observed for one minute to record the highest and lowest rungs reached by the paws of the mice. The average of these two records was used as the record for each mouse (highest and lowest records were 27 and 0, respectively). Immediately after the 1 minute climbing observation period, each mouse was left in a circular swimming tank for 2 minutes and the number of swimming was counted. The tank is 15 cm high and 28 cm in diameter. Circular obstructions 10.5 cm in diameter and 17 cm in height were placed in the center of the tank to create a circular swimming channel with a butterfly of 8.75 cm. The water height was 5.5 cm and the water was kept at room temperature. Marked on the side of the tank 180 degrees above the floor. The number of "swimming" was recorded when the mouse swam from one mark to the other. Mice were observed through a ceiling mirror to record the number of 180 ° swimming for each mouse. In this test, when a given dose of test compound is used, activity is shown by a decrease in climbing records and an increase in swimming records. Representative results for the lowest dose value in this test were 1.3 mg / kg for the compound of Example 49 and 20 mg / kg for the compound of Example 5.

In general, a compound was considered to be active when it gave an IC ₅₀ value of 500 nM or less in Test A and / or exhibited activity after oral administration of 40 mg / kg or less in Test B.

Hereinafter, the present invention will be described in detail with reference to examples, but the following examples do not limit the protection scope of the present invention. Unless otherwise stated, the following was carried out.

(i) The temperature is expressed in degrees Celsius (° C.) and the operation was carried out at room temperature or ambient temperature, ie 18-25 ° C.

(ii) The solvent was evaporated using a rotary evaporator at a batch temperature of 60 ° C. or less under reduced pressure (600-4000 Pascal, 4.5-30 mmHg).

(iii) Flash chromatography was performed on Merck Kieselgel (Art 9385) or Baker Flash silica gel. Thin layer chromatography (TLC) was performed on Analtech 0.25 mm silica gel GHLF plate (Art. 21521).

(iv) High Pressure Liquid Chromatography (HPLC) for enantiomeric purity measurement analysis of chiral compounds was carried out on 25 cm x 4.6 mm Chiralcel from JT Baker, Inc. Performed using either OD or 15 cm x 4.6 mm Ultron Ovomucoid columns, and for most reactions and final products HPLC analysis was performed on 25 cm x 4.6 mm Supelcosil available from Supelco, State College, Pennsylvania, USA. LC-8-DB column, 25 cm x 4.6 mm Supelcosil LC-18-DB column, or 25 cm × 4.6 mm Zorbax Performed on RX column.

(v) In general, the reaction procedure was followed by TLC and / or HPLC and the reaction time is described for specific examples only.

(vi) the melting point is not corrected, (dec) indicates decomposition, the given melting point is the melting point obtained from the material prepared as described in the examples, and due to polymorphism the separation of materials with different melting points in some manufacturing methods It was.

(vii) All final products were found to be nearly pure by TLC and / or HPLC and had reasonable nuclear magnetic resonance (NMR) spectra and trace element analysis data.

(vii) Yields are described for specific examples only.

(ix) Decompression was described as absolute pressure in Pascals (Pa), and other pressures as gauge pressures in bar (bar).

(x) Chemical symbols have their usual meanings. The following abbreviations were used. v (volume), w (weight), mp (melting point), L (liters), mL (milliliters), g (grams), mmol (millimoles), mg (milligrams), min (minutes), h (hours).

(xi) The solvent ratio is described in volume units. Ie, volume ratio (v / v).

Example 1

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol]

3-bromopyridine (0.540 mL, immediately after distillation under nitrogen in a low temperature (-90 ° C.) solution of n-butyllithium (2.5 M in hexane, 2.40 mL, 6.0 mmol, 1.5 equivalents) in tetrahydrofuran (40 mL). 5.6 mmol, 1.4 equiv) was added. The metal-halogen exchange reaction was warmed to -75 ° C and maintained for 1.5 hours. In the meantime, a dark green solution in the form of fine particles was formed. A solution of 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (1.35 g, 4.0 mmol) in tetrahydrofuran (10 mL) Was added dropwise and the color of the solution became very bright and dark yellow. The reaction was allowed to warm to room temperature over 1 hour and quench the reaction with water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The reaction mixture was purified by flash chromatography on silica gel (80 mL, eluent: ethyl acetate) to yield 1.35 g (81%) of the title compound as a white solid.

TLC analysis (R _f 0.20, ethyl acetate).

1 H NMR (D ₆ -DMSO, 300 MHz) 8.69 (br s, 1 H), 8.41 (d, J = 4.5 Hz, 1 H), 7.83 (dt, J = 8.0 Hz, 1 H), 7.29 (m, 5H), 6.95 (m, 3H), 5.05 (s, 1H), 4.35 (s, 1H), 3.41 (m, 2H), 3.34 (s, 1H), 2.75 (m, 4H), 1.92 (m, 2H), 1.62 (m, 2H)

MS (CI, CH4) m / z 417 (M + 1, 100), 419 (36), 445 (M + 29, 15), 399 (15)

The free base was dissolved in diethyl ether containing a small amount of methylene chloride and acidified with etheric HCl, followed by further dilution of the hydrochloride suspension with an additional amount of ether. The salts were filtered off, washed with clean ether and dried in vacuo (50 ° C., 13 Pascals, 18 hours) to give a white solid.

mp 225-228 ° C (decomposition)

Elemental Analysis for C ₂₆ H ₂₅ ClN ₂ 0.2.1HCl.H ₂ O:

Theoretical: C, 61.04; H, 5.73; N, 5.48

Found: C, 60.91; H, 5. 64; N, 5.29

The starting material piperidinone was prepared as follows.

a. 2-chloroanthracene

A stirred suspension of 2-chloroanthraquinone (1260 g, 5.19 mol) in concentrated ammonium hydroxide (7.5 L) and water (2.5 L) was warmed to 40 ° C. Zinc powder (845 g, 12.93 mol) was added all at once and the color turned dark red. After the mixture was stirred at 50 ° C. for 45 minutes, zinc powder (845 g) was further added and treated carefully. After addition, the stirred mixture was heated slowly to 90 ° C. over 3 hours and maintained at 90-95 ° C. (red discolored) for 2 hours. TLC analysis (silica gel, hexane: methylene chloride (3: 1)), anthraquinone (R _f 0.35) was found to be completely converted to the desired anthracene (R _f 0.80). The reaction mixture was cooled to rt and stirred overnight. The cooled mixture was treated with methylene chloride (4 L), stirred for 2 hours and then filtered through celite to remove excess zinc. The filter cake was washed with methylene chloride (6 × 1 L). The methylene chloride layer was separated from the aqueous layer and then treated with 6N hydrochloric acid (3 L) and stirred for 2 hours. The first product of 2-chloroanthracene was collected by filtration and washed with water (4 × 1 L). Vacuum drying afforded 804.6 g (mp 220-221 ° C.) as a pale yellow crystalline product. The methylene chloride portion in the filtrate was concentrated in vacuo to 10% of original volume. Concentration gave 158.5 g of the desired compound further, with a total yield of 963.1 g (87.2%).

b. 2-chloro-9-prylanthracene

N-methylformanilide (2.45 kg, 18.12 mol) was treated with phosphorus oxychloride (2.66 kg, 17.35 mol) over 40 minutes at ambient temperature. The intermediate Vilsmeier complex was stirred for 2 hours at room temperature and then treated with 2-chloroanthracene (as described in Example 1a) (963 g, 4.53 moles) and o-dichlorobenzene (1.0 L). The pale yellow mixture formed was slowly heated to 9 ° C. over 1.5 h at which time exotherm occurred and the reaction temperature rose to 115 ° C. After the heating was stopped until the exotherm had settled, the mixture was heated at 90 ° C. for 9 hours and then cooled. TLC analysis results (silica gel, ethyl acetate: hexane 1: 4), small amount of unreacted anthracene (R _f 0.90), small amount of 3-chloro isomer (R _f 0.65) and main component 2-chloro isomer (R _f 0.58) ) Was found to exist. The cooled reaction mixture was poured into ice / water (27 L) to precipitate dark brown tar. The aqueous layer was decanted from tar and extracted with methylene chloride (5 × 2 L). The extracts were combined and used to redissolve the tar. The methylene chloride solution was washed with 3N hydrochloric acid (4 x 1.5 L) followed by water (2 L) and dried over magnesium sulfate. The extract was filtered and then eluted with methylene chloride through a silica gel layer and filtered under pressure until all desired compound was recovered. The eluate was concentrated on a rotary evaporator to give a slurry of pale yellow crystals (slurry in o-dichlorobenzene). The crystals were collected by filtration, washed with diethyl ether (2 × 500 mL) and then dried in vacuo to give 619.7 g (56.9%) of the desired 2-chloro-9-formylanthracene (mp 148-150 ° C.).

1 H NMR (CDCl ₃ ) 11.35 (s, 1H), 9.02 (d, J = 0.9 Hz, 1H), 8.81 (d, J = 8.9 Hz, 1H), 8.56 (S, 1H), 7.98 (m, 1H) , 7.90 (d, J = 8.9 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H)

c. 12-acetoxy-2-chloro-9-formyl-9,10-dihydro-9,10-ethanoanthracene (E and Z isomers)

A mixture of 2-chloro-9-formylanthracene (as described in Example 1b) (100.0 g, 0.415 mol) and vinyl acetate (400 mL, 374 g, 4.34 mol) was placed in a stainless steel bomber (PARR) at 200 ° C. (Sand bath temperature) was heated for 24 hours and then cooled. The reaction mixture was concentrated on a rotary evaporator to remove excess vinyl acetate, leaving the crude product as a tan crystalline solid. This crude product was combined from several batches to give 670.0 g (2.78 moles) of 2-chloro-9-propylanthracene. Trituration with diethyl ether (1.0 L) and filtration gave an off-white crystalline solid which was washed with diethyl ether (2 x 300 mL) and dried in vacuo to give 629.0 g (69.1%) of the title compound (mp). 145-153 ° C.).

The filtrate and washings were evaporated to afford a thick brown oil, which was purified by column chromatography on silica gel using a solvent mixture of methylene chloride: hexane (1: 1) as eluent. The recovered solid was recrystallized from diethyl ether: hexane (1: 1, 400 mL) to obtain 175.5 g (19.3%) of the title compound.

d. 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracenecarboxylic acid (E and Z isomers).

12-acetoxy-2-chloro-9-formyl-9,10-dihydro-9,10-ethanoanthracene (described in Example 1c) dissolved in acetone (8.0 L) (629.0 g, 1.925 mol) ) Was treated with Jones reagent (1.50 L, about 1.93 moles, prepared as described in Fieser & Fiser Vol. 1: pp142) at 10-20 ° C. over 1 hour. After addition of the Jones reagent the reaction mixture was stirred for 4 hours at room temperature. TLC analysis (silica gel, methylene chloride) revealed that the aldehyde (R _f 0.73) was consumed completely. Isopropanol (100 mL) was added and the reaction stirred for 18 hours to remove excess Jones reagent, resulting in a white suspension of black green sludge (chromium salt). The white supernatant was decanted and the sludge was washed with acetone (5 x 500 mL). The acetone washes were combined with the supernatant and concentrated on a rotary evaporator until the final volume reached 2 L. The residue was poured into ice / water (10 L) and vigorously stirred for 5 hours to yield an off white solid. The material was collected by filtration, washed with water (3 × 1 L) and dried in vacuo to yield 665.3 g (quantitative) yield of the desired product carboxylic acid (mp 270-273 ° C. (decomposition)).

e. 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracene-9-ylcarbonyl chloride (E and Z isomers)

12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracenecarboxylic acid (as described in Example 1d) (665.0 g, 1.94 mol) was added to toluene (8.0 L). Suspended in. Thionyl chloride (400 g, 3.36 moles) was added all at once at room temperature followed by the addition of N, N-dimethylformamide in catalytic amount (2 mL). The mixture was slowly heated to reflux (80 ° C.) over 1 h and then left under reflux for 8 h to give a clear dark brown solution. The cooled reaction mixture was concentrated on a rotary evaporator under pump vacuum to remove toluene. Crude acid chloride was separated as a solid in the form of a brown wax and used for the subsequent reaction. A small amount of sample in the material was dried under high vacuum to obtain a sample for spectral analysis.

f. 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylcarbonyl azide (E and Z isomers).

Crude 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracene-9-ylcarbonyl chloride (as described in Example 1e) (804 g, about 1.94 moles) ) Was dissolved in acetone (8.0 L) and the resulting solution was cooled to -5 ° C using an ice / methanol bath. To the stirred mixture was treated by addition of aqueous sodium azide solution (380 g, 5.84 moles in 1.0 L of water) over 30 minutes. The tan suspension formed was stirred at 0 ° C. for 3 hours and then warmed to room temperature. The mixture was concentrated on a rotary evaporator using a pump vacuum at 15-20 ° C. to remove acetone. The residue was partitioned between moles (5 L) and toluene (5 L) and stirred for 1 hour and then filtered. The biphasic filtrate was separated and the aqueous portion was extracted with toluene (5 × 1 L). Toluene extract was used to redissolve the filter cake, which had been previously separated. The toluene solutions were combined and washed with brine solution (2 L) and then dried over magnesium sulfate. Toluene was filtered off and then concentrated to 1/2 volume on a rotary evaporator at 15-20 ° C. under pump vacuum. Concentration resulted in a toluene solution of acyl azide (the yield is estimated to be quantitative). This solution was used for the subsequent reaction. A small amount of sample in solution was evaporated under high vacuum to separate a sample of spectral analysis acyl azide, which was an off white viscous solid.

g. 12-acetoxy-2-chloro-9-isocyanato-9,10-dihydro-9,10-ethano anthracene (E and Z isomers).

The toluene solution of crude acyl azide (about 713.5 g, 1.94 moles in 6.0 L of toluene) separated in the previous step was slowly heated to 65 ° C. over 30 minutes. At this time, nitrogen was rapidly foamed and exotherm occurred, and the temperature of the reaction mixture rose to 95 ° C. The heating mantle was removed (30 minutes) until the exotherm had settled, then the reaction was heated under reflux for 3 hours before cooling. Toluene was removed on a rotary evaporator using a pump vacuum to separate crude isocyanate (738.5 g, 112% of theory) as a thick tan oil. This material was used for the next step reaction without further purification. The oil sample was dried under high vacuum to prepare a sample for spectral analysis.

h. 9-amino-2-chloro-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (E and Z isomers).

The crude isocyanate (738.5 g, 1.94 mol) obtained from the previous step was dissolved in anhydrous ethanol (7.0 L) to give a pale yellow solution. The stirred solution was treated by adding 20% aqueous sodium hydroxide solution (800 g, 20.0 moles in 4.0 L of water) at once at room temperature. The reaction mixture soon turned reddish brown as soon as the base was added. The mixture was heated at reflux for 8 hours and then cooled. TLC analysis (silica gel, methylene chloride) revealed that the isocyanate (R _f 0.80) was consumed completely. The reaction mixture was concentrated on a rotary evaporator to remove ethanol and the aqueous suspension of remaining product was extracted with methylene chloride (3 x 5 L). The combined extracts were washed with water (2 L) and brine solution (1 L) and then dried over magnesium sulfate. Filtration and removal of solvent in vacuo gave crude aminoalcohol as a sticky tan solid. Trituration with diethyl ether (1.0 L) afforded 445.8 g (84.5%) of pure compound as a creamy powder (mp 164-167 ° C).

i. 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene

9-amino-2-chloro-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (described in Example 1h) (445.5 g 1.64 moles) was dissolved in glacial acetic acid (4.0 L) The solution formed was cooled to 10 ° C. Sodium nitrite solution in water (1.4 L) was added to the reaction mixture over 1.75 hours. The temperature of the mixture was kept at 10 ° C. during the addition of nitrite and for 4 hours thereafter. The mixture was then stirred overnight and warmed to room temperature. TLC analysis results (silica gel, toluene: ethyl acetate (4: 1)), aminoalcohol (R _f 0.12) was 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene ( R _f 0.80). The reaction mixture was diluted with water (4 L) to precipitate reddish brown tar. The aqueous supernatant was decanted from tar and diluted with the same amount of crushed ice, then the pH was adjusted to 5-6 with solid sodium hydroxide. The aqueous mixture formed was extracted with ethyl acetate (3 × 1.5 L). The tar was redissolved using the combined ethyl acetate extracts and the resulting solution was washed with brine (2 × 1 L) and dried over magnesium sulfate. The solvent was removed in vacuo after filtration to give the crude product as a thick brown oil. This material was purified by column chromatography on silica gel using a solvent mixture of methylene chloride: hexane (1: 1) as eluent. A thick yellow oil (311.7 g, 74.6%) was obtained that crystallized upon standing. Trituration with diethyl ether: hexane (1: 6, 700 mL) afforded 224.1 g (53.6%, mp 91-92 ° C) of an off-white crystalline solid as the first product of the pure title compound.

The material was recovered from the mother liquor and the wash liquor and refined by column chromatography as described above to give 65.0 g (15.5%) of the title compound.

j. 2-Chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

Cooled (0 ° C.) solution of 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in Example 1i) (20.0 g, 78.5 mmol) in acetone (260 mL) Jones reagent (24 mL, 27 g chromium trioxide, 23 mL of water was diluted with 100 mL of reagent solution) was added in portions. Reagent was added until orange remained. The reaction containing a significant amount of reduced chromium salt was warmed to room temperature. The solvent was removed in vacuo and replaced with water (300 mL) saturated with sodium chloride. The aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were extracted with 2.5N NaOH (3 × 400 mL). The basic aqueous extract was acidified with 3N HCl, saturated with sodium chloride and extracted with ethyl acetate (4 x 300 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an off white solid. 26.66 g (quantitative yield) of the title compound were obtained. No further purification was necessary.

k. 1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -piperidin-4-ol

Thionyl chloride in a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracene carboxylic acid (as described in Example 1j) (6.51 g, 24.1 mmol) in toluene (70 mL). (2.28 mL, 31.3 mmol, 1.3 equiv) was added. The gas was bubbled into the mineral oil foaming device while the reaction was heated to reflux. The reaction system reached steady state within 40 minutes, at which time the reaction system was slightly cooled and 4-hydroxy piperidine (6.08 g, 60.3 mmol, 2.5 equiv) was added in portions. A significant amount of heat was generated and the color of the reaction darkened. The suspension was heated to reflux for 2 hours, cooled to room temperature and stirred for 18 hours. The reaction was diluted with ethyl acetate (200 mL) and washed with 3N HCl (2 × 100 mL), 2.5N NaOH (2 × 100 mL) and saturated brine (200 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to an oil. 6.95 g (82%) of the title compound were obtained as a viscous oil. No further purification was necessary.

l. 1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) piperidin-4-ol (as described in Example 1k) in diethyl ether (200 mL) To a cooled (0 ° C.) suspension of lithium aluminum hydride (1.49 g, 39.2 mmol, 8 equivalents of hydride) was added in portions under nitrogen. The suspension was stirred at 0 ° C. for 30 minutes and allowed to warm to room temperature. After 18 hours at room temperature, excess reagent was carefully quenched in the following order. Water (1.5 mL), 2.5N NaOH (1.5 mL) and additional amount of water (4.5 mL). The suspension was vigorously stirred until the aluminum salt became a granular white solid. The suspension was diluted with ethyl acetate (100 mL), dried over a small amount of anhydrous magnesium sulfate and filtered. The filter cake was washed with ethyl acetate. The solvent was removed to give 6.16 g (92%) of the title compound as a white solid. No further purification was necessary. TLC analysis (R _f 0.15, 50% ethyl acetate in hexanes).

m. 1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone

To a cooled (-78 ° C) solution of oxalyl chloride (3.06 mL, 35.1 mmol, 2 equiv) in methylene chloride (100 mL) was distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 equiv) under nitrogen. After 10 minutes, 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol (as described in Example 1l) (5.96 g , 17.5 mmol) was added in the form of methylene chloride solution (10 mL). The reaction was stirred at −78 ° C. for 30 minutes before triethylamine (19.6 mL, 140 mmol, 8 equiv) was added. The cold bath was removed and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3 × 100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The crude reaction mixture was purified by flash chromatography on silica gel (400 mL, eluent: 20% ethyl acetate in hexanes) to give 5.53 g (93%) of the title compound. TLC analysis (R _f 0.21, 20% ethyl acetate in hexanes).

The chloromethanoanthracene acid was digested as follows.

n. (9S, 10S) Optical resolution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid.

2-Chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 1j) in ethyl acetate (1.5 L) and methanol (75 mL) (100 g, 0.37 mol) (1S, 2S)-(+)-Pseudoephedrine (61.1 g, 0.37 mole) solid was added to the racemic solution. The mixture was heated to reflux with sufficient stirring and kept at reflux for 30 minutes and then at 25 ° C. Cool slowly. After at least 2 hours the slurry was filtered and washed with ethyl acetate to give concentrated diastereomeric salts (88.6 g, 0.20 mol, 55%, diastereomeric ratio 80:20 as determined by HPLC). The concentrated salt was slurried in 3% methanolic ethyl acetate (2.74 L), warmed to reflux and left at reflux for 30 minutes. The slurry was slowly cooled to 25 ° C., stirred for 2 hours, filtered and washed with ethyl acetate to give a further concentrated salt (70 g, 0.16 mole, 79%, diastereomeric ratio 95: 5 as determined by HPLC). The concentrated salt was treated with 5% methanolic ethyl acetate using the same method to give a highly concentrated salt (60.0 g, 0.14 mol, 85%, diastereomeric portion 99: 1 as determined by HPLC). This salt was added to water (1 L) and the resulting suspension was acidified to pH 2-3 with concentrated hydrochloric acid (15 mL) and then extracted with diethyl ether (3 x 500 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to give an oil. Hexane was added and concentrated in vacuo to afford an enantiomeric concentrated acid (36 g, 0.13 mol, 98% recovery, 99: 1 enantiomer ratio as measured by HPLC) as a white solid. (9S, 10S) -2-chloro-9,10-dihydro-9,10-methano-9-, a pure enantiomer as a white solid, recrystallized from a mixture of hexane (360 mL) and cyclohexane (720 mL). Anthracene carboxylic acid (30 g, 0.11 mol, 81%) was obtained.

mp 172-173 ℃

Rotation α (sodium D): + 101 ° (c = 2, CHCl ₃ ).

Elemental Analysis for C ₁₆ H ₁₁ C1O ₂ :

Theoretical: C, 70.99; H, 4.10

Found: C, 70.81; H, 4.21

1 H NMR 7.48-7.62 (m, 2H), 7.27-7.35 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.90-7.10 (m, 3H), 4.35 (s, 1H), 2.80- 2.95 (m, 2 H).

HPLC analysis: Column: Ultron Ovomucoid (ES-OVM) 15 cm × 6 mm, Eluent: 15% acetonitrile / 85% aqueous KH 2 PO 4 buffer solution (10 mM) adjusted to pH 5.5 with potassium hydroxide. Flow rate: 1 mL / min, wavelength: 230 nm, retention time: (+) enantiomer 15.4 minutes / (-) enantiomer 19.6 minutes.

(9R, 10R) 2-Chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid was digested as follows.

o. Optical resolution of (9R, 10R) 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

(9R, 10R) 2-Chloro-9,10-dihydro-9 using a method similar to that described in Example 1n, except for using (1R, 2R)-(-)-pseudoephedrine as a disintegrant , 10-methano-9-anthracenecarboxylic acid was obtained.

mp 169-170 ℃

Rotational α (sodium D): 100.8 ° (c = 2.0 CHCl ₃ )

Elemental Analysis for C ₁₆ H ₁₁ ClO ₂ :

Theoretical: C, 70.99; H, 4.10

Found: C, 70.75; H, 4.18

1 H NMR 7.48-7.64 (m, 2H), 7.27-7.35 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.90-7.12 (m, 3H), 4.36 (s, 1H), 2.80- 2.95 (m, 2 H).

Example 2

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (6-quinolinyl) piperidin-4-ol

The title compound was obtained in 63% yield as a white solid using a method similar to that described in Example 1, except using 7-bromoquinoline.

mp 210-215 ° C. (decomposed).

Free base: 1 H NMR (CDCl ₃ , 250 MHz) 8.87 (dd, J = 1.6, 4.2 Hz, 1H), 8.14 (d, J = 7.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 1.9Hz, 1H), 7.86 (dd, J = 2.0, 8.8 Hz, 1H), 7.38 (dd, J = 4.2, 8.3 Hz, 1H), 7.20 (m, 4H), 6.95 (m , 3H), 4.26 (s, 1H), 3.46 (s, 2H), 2.87 (m, 2H), 2.78 (m, 2H), 2.64 (d, J = 1.4 Hz, 2H), 2.24 (m, 2H) , 1.89 (s, 1H), 1.80 (m, 2H)

MS (CI, CH 4) m / z 467 (M + l, 100), 469 (38), 495 (M + 29, 19), 449 (15)

Hydrochloride: Elemental Analysis for C ₃₀ H ₂₇ N ₂ OCl.2HCl.H ₂ O:

Theoretic value: C, 64.58; H, 5. 60; N, 5.02

Found: C, 64.18; H, 5.54; N, 4.87

Example 3

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-quinolinyl) piperidin-4-ol

The title compound was obtained in 50% yield as a white solid using a method similar to that described in Example 1, except using 3-bromoquinoline.

mp 215-217 ° C. (decomposed).

Hydrochloride: Elemental analysis for C ₃₀ H ₂₇ N ₂ OCl.2HCl.H ₂ O:

Theoretic value: C, 64.58; H, 5. 60; N, 5.02

Found: C, 64.24; H, 5.49; N, 4.92

Example 4

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-thiazyl) piperidin-4-ol

The title compound was obtained in 78% yield as a white solid using a method similar to that described in Example 1, except using 2-bromothiazole.

Hydrochloride: Elemental Analysis for C ₂₄ H ₂₃ ClN ₂ OS.2HCl.0.5H ₂ O:

Theoretical: C, 57.09; H, 5. 19; N, 5.55

Found: C, 56.94; H, 5.03; N, 5.23

Example 5

1- (9,10-dihydro-9,10-methanenoanthrace-9-ylmethyl) -4- (3-pyridyl) -piperidin-4-ol

Using a method similar to that described in Example 1, except starting with 1- (9,10-dihydro-9,10-methanenoanthracene-9-ylmethyl) -4-piperidinone The title compound was obtained in 66% yield as a white solid.

Hydrochloride: Elemental Analysis for C ₂₆ H ₂₆ N ₂ O.2HCl.0.7H ₂ O:

Theoretic value: C, 66.72; H, 6. 33; N, 5.99

Found: C, 66.76; H, 6. 60; N, 5.87

The starting material piperidinone was prepared as follows.

a. 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

9-formyl-9,10-dihydro-9,10-methanoanthracene (literally prepared method: M.Sunagawa et al., Chem. Prarm. Bull.Vol. 27 (1979) pp 1806-1812, US Patent 4,224,344, Sunagawa et al., Sumitomo, Ltd., Sept. 23, 1980, US Pat. No. 4,358,620 Sunagawa et al., Sumitomo, Ltd., Nov. 9,1982) Using a method similar to that described in 1j, the title compound was obtained in 80% yield as a white solid.

b. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) piperidin-4-ol

Using a method similar to that described in Example 1k, except that 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 5a) was used as the starting material, The title compound was obtained in quantitative yield as a viscous oil.

c. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

Except that starting with 1- (9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) piperidin-4-ol (described in Example 5b) as starting material Using a method similar to that described in Example 1 l, the title compound was obtained in 88% yield as a white solid.

d. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone

Example, except for using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol (described in Example 5c) as starting material Using the method analogous to that described for 1 m, the title compound was obtained in 80% yield as a white solid.

Example 6

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-furanyl) -piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and using 3-bromofuran Except for the above, the title compound was obtained in a 71% yield as a white solid using a method similar to that described in Example 1.

Hydrochloride: Elemental analysis for C ₂₅ H ₂₅ NO ₂ .HCl.0.1H ₂ O:

Theoretic value: C, 73.28; H, 6. 44; N, 3.42

Found: C, 73.24; H, 6. 49; N, 3.30

Example 7

4- (5-Bromo-2-methoxy-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

3.5-dibromo-2- with 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material Except for using methoxypyridine (a method of preparation in literature: JM Barger, JK Dulworth, MT Kenny, R. Massao, JK Daniel, T. Wilson.RT Sargent J. Med. Chem. 1986, 29, 1590) Using the method analogous to that described in Example 1, the title compound was obtained in 63% yield as off-white solid.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₇ BrN ₂ O ₂ .HCl:

Theoretical: C, 61.43; H, 5. 35; N, 5.31

Found: C, 61.42; H, 5. 42; N, 5.25

Example 8

4- (5-chloro-2-methoxy-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

3-bromo-5-chloro, starting with 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (as described in Example 5d) The title compound was obtained in 25% yield as a white solid using a method similar to that described in Example 1 except using 2-methoxypyridine.

Hydrochloride: elemental analysis for C ₂₇ H ₂₇ ClN ₂ O ₂ .HCl.0.6H ₂ O:

Theoretic value: C, 65.61; H, 5.95; N, 5.67

Found: C, 65.48; H, 5. 76; N, 5.58

The starting material methoxypyridine derivative was prepared as follows.

a. 5-chloro-2-methoxypyridine

Sodium hydride (60% in mineral oil, 5.50 g, 115 mmol, 2 equiv) was added dropwise to anhydrous methanol (distilled from Mg, 25 mL) under nitrogen atmosphere. 2.5-dichloropyridine (10.0 g, 68 mmol) was added to this solution. After the resulting solution was refluxed for 18 hours, the reaction was cooled and the excess sodium bicarbonate was treated as a solid. The reaction was allowed to solidify and concentrated to 50% of its initial volume and the solution solidified. The solid was washed with hexane and the washes were combined and concentrated to give an oil. Purification by reduced pressure distillation (102 DEG C, 2400 Pascal) gave 6.30 g (65%) of the title compound as a colorless oil.

MS (CI, CH 4) m / z 144 (M + l, 100), 146 (44), 172 (M + 28, 19), 124 (9).

b. 3-bromo-5-chloro-2-methoxypyridine

The title compound was obtained in 41% yield using a method similar to that described in Example 7, except for using 5-chloro-2-methoxypyridine (described in Example 8a) as the starting material.

MS (CI, CH4) 222 (M + 1, 74), 224 (100), 226 (24), 250 (5), 252 (6), 254 (1)

Example 9

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-quinolinyl) -piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and using 3-bromoquinoline Except for the above, the title compound was obtained in a 44% yield as a white solid using a method similar to that described in Example 1.

Hydrochloride: Elemental Analysis for C ₃₀ H ₂₈ N ₂ O.2HCl.2.5H ₂ O:

Theoretical: C, 65.45; H, 6. 41; N, 5.09

Found: C, 65.47; H, 5.93; N, 4.94

Example 10

4- (4-isoquinolinyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and 4-bromoisoquinoline The title compound was obtained in 53% yield as a white solid using a method similar to that described in Example 1 except that.

Hydrochloride: Elemental Analysis for C ₃₀ H ₂₈ N ₂ O.0.2.5HCl.H ₂ O:

Theoretical: C, 66.50; H, 6.05; N, 5.12

Found: C, 66.37; H, 5.89; N, 5.03

Example 11

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-5-pyridyl) piperidin-4-ol

5-bromo-2-meth as starting material with 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) Using the method similar to that described in Example 1, except using oxypyridine, the title compound was obtained in 81% yield as a white solid.

MS (CI, CH 4) m / z 413 (M + l, 100), 441 (M + 29, 12), 395 (19).

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O ₂ .2HCl.0.5H ₂ O:

Theoretic value: C, 65.59; H, 6. 32; N, 5.67

Found: C, 65.48; H, 6. 14; N, 5.35

The starting material methoxypyridine derivative was prepared as follows.

a. 5-bromo-2-methoxypyridine

The title compound was obtained in 73% yield using a method similar to that described in Example 8a, except for using 2,5-dibromopyridine as the starting material.

Example 12

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-pyrimidinyl) -piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as a starting material and using 5-bromopyridine Except for the above, the title compound was obtained in 60% yield as a white solid using a method similar to that described in Example 1.

Hydrochloride: Elemental Analysis for C ₂₅ H ₂₅ N ₃ O.HCl.0.4H ₂ O:

Theoretical: C, 70.30; H, 6. 32; N, 9.84

Found: C, 70.33; H, 6. 21; N, 9.77

Example 13

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (6-methoxy-2-pyridyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as a starting material and 2-bromo-6-meth Using the method analogous to that described in Example 1, except using oxypyridine, the title compound was obtained in 98% yield as a white solid.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O ₂ .HCl.0.6H ₂ O:

Theoretic value: C, 70.53; H, 6. 62; N, 6.09

Found: C, 70.22; H, 6. 46; N, 6.04

Example 14

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-thiazyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as a starting material and 2-bromo-thiazole Using the method analogous to that described in Example 1, except using, the title compound was obtained in 77% yield as an off-white solid.

Hydrochloride: Elemental Analysis for C ₂₄ H ₂₄ N ₂ OS.2HCl:

Theoretical: C, 62.47; H, 5.68; N, 6.07

Found: C, 62.58; H, 5.87; N, 5.76

Example 15

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-thiazyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and 2-bromo-thiophene Using the method analogous to that described in Example 1, except using, the title compound was obtained in 81% yield as a white solid.

Hydrochloride: Elemental Analysis for C ₂₅ H ₂₅ NOS.1.6HCl.H ₂ O:

Theoretical: C, 64.73; H, 6. 21; N, 3.02

Found: C, 64.72; H, 5. 86; N, 2.93

Example 16

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-pyridyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and 2-bromo-pyridine The title compound was obtained in 66% yield as a white solid using a method similar to that described in Example 1 except that.

Hydrochloride: Elemental Analysis for C ₂₆ H ₂₆ N ₂ O.2HCl.0.1H ₂ O:

Theoretical: C, 68.30; H, 6. 22; N, 6.13

Found: C, 68.17; H, 6. 21; N, 6.09

Example 17

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-methoxyphenyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and 3-bromo-inisol Using a method similar to that described in Example 1 except for using, the hydrochloride of the title compound was obtained as a white solid in 59% yield.

mp 260-261 ° C.

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₉ NO ₂ .HCl.0.4H ₂ O:

Theoretic value: C, 73.88; H, 6. 82; N, 3.08

Found: C, 73.87; H, 6. 70; N, 3.14

Example 18

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-methoxyphenyl) -piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and using 4bromo-inisol A hydrochloride of the title compound was obtained in 72% yield as a white solid, except using a method similar to that described in Example 1.

Example 19

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxyphenyl) -piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as a starting material and 2-bromo-inisol Using the method analogous to that described in Example 1, except using, the title compound was obtained in 43% yield as a white solid.

mp 290-293 ° C.

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₉ NO ₂ .HCl.0.3H ₂ O:

Theoretic value: C, 74.17; H, 6. 80; N, 3.08

Found: C, 74.01; H, 6.83; N, 3.04

Example 20

1- (9,10-dihydro-9,10-methanenoanthrace-9-ylmethyl) -4- (2-dimethylaminomethylphenyl) -piperidin-4-ol

2-bromo-N, N starting with 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) A hydrochloride of the title compound was obtained in 36% yield as a white solid using a method similar to that described in Example 1 except using dimentylbenzylamine.

Example 21

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-phenylpiperidine

Excess 3A molecular sieve immediately after activation in methanol solution of 9-formyl-9,10-dihydro-9,10-methanoanthracene (described in Example 5a) (5.00 g, 22.7 mmol) 10 g) was added under a nitrogen atmosphere. 4-phenylpiperidine (4.57 g, 28 mmol, 1.25 equiv) was added followed by sodium cyanoborohydride (1.43 g, 22.7 mmol) in quarter portions over 1.3 h. The suspension of molecular sieve and reagent formed was stirred for 3 days at room temperature. The reaction was treated with 2.5N NaOH (100 mL) and the aqueous phase was extracted with ethyl acetate (1 × 400 mL). The organic phase was washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (300 mL, eluent: 50% methylene chloride in hexanes) to recover 1.20 g (15%) of the title compound.

The free base was dissolved in a minimum amount of methanol and chloroform, acidified with etheric HCl, and then the hydrochloride formed was precipitated by dilution with ether. The solid was filtered off, washed with clean ether, dried in vacuo (50 ° C., 10 pascal, 18 hours) to give a solid.

mp> 300 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₇ N.HCl.0.5H ₂ O:

Theoretical: C, 78.91; H, 7. 11; N, 3.41

Found: C, 78.91; H, 6.92; N, 3.38

Example 22

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-chlorophenyl) -piperidin-4-ol

The title compound hydrochloride was obtained as a white powder in 19% yield using a method similar to that described in Example 21, except using 4- (4-chlorophenyl) -4-hydroxypiperidine.

mp 281-285 ° C.

Elemental Analysis for C ₂₇ H ₂₆ ClNO.HCl.0.25H ₂ O:

Theoretic value: C, 70.97; H, 6.06; N, 3.06

Found: C, 71.28; H, 6.03; N, 3.02

Example 23

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-phenylpiperidin-4-ol

The title compound hydrochloride was obtained as a white powder in 18% yield using a method similar to that described in Example 21, except using 4-hydroxy-4-phenylpiperidine.

mp 273-275 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₇ NO.HCl:

Theoretic value: C, 77.58; H, 6.75; N, 3.35

Found: C, 77.51; H, 6.79; N, 3.32

1 H NMR (D ₆ -DMSO, D-TFA): 7.72-7.23 (m, 9H), 7.01 (m, 4H), 4.49 (s, 3H), 3.64 (m, 4H), 2.76 (s, 2H), 2.50 (m, 2H), 1.82 (d, J = 13.9 Hz, 2H)

MS (CI, CH 4) m / z 383 (30), 382 (M + l, 100), 381 (14), 380 (14), 364 (25).

Example 24

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-trifluoromethyl phenyl) piperidin-4-ol

Using the method analogous to that described in Example 21, except using 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine, the title compound hydrochloride was obtained as a white powder in 44% yield. Got it.

mp 268-270 ° C.

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₆ F ₃ NO.HCl.0.25H ₂ O:

Theoretic value: C, 68.56; H, 5.65; N, 2.86

Found: C, 68.74; H, 5.63; N, 2.81

Example 25

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-fluorophenyl) -piperidin-4-ol

The title compound hydrochloride was obtained as a white powder in 26% yield using a method similar to that described in Example 21, except using 4- (4-fluorophenyl) -4-hydroxypiperidine. .

mp 262-266 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₆ FNO.HCl:

Theoretic value: C, 74.38; H, 6. 24; N, 3.21

Found: C, 74.41; H, 6. 24; N, 3.17

Example 26

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-chlorophenyl) piperidin-4-ol

Except for using 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (Example 1i) and 4- (4-chlorophenyl) -4-hydroxypiperidine Using the method analogous to that described in Example 21, the title compound hydrochloride was obtained as a white powder in 29% yield.

mp 261-263 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₅ Cl ₂ NO.HCl:

Theoretic value: C, 66.61; H, 5. 38; N, 2.87

Found: C, 66.41; H, 5. 44; N, 2.80

.

Example 27

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-fluorophenyl) -piperidin-4-ol

The use of 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (Example 1i) and 4- (4-fluorophenyl) -4-hydroxypiperidine Using the same method as described in Example 21, except the title compound hydrochloride was obtained in the form of a white powder in 27% yield.

mp 280-281 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₅ ClFNO.HCl.0.5H ₂ O:

Theoretical: C, 67.64; H, 5.68; N, 2.92

Found: C, 67.70; H, 5.40; N, 2.84

Example 28

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (phenylpiperidin) -4-ol

Example, except using 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (Example 1i) and 4-hydroxy-4-phenylpiperidine Using a method similar to that described in 21, the title compound hydrochloride was obtained as a white powder in 32% yield.

mp 260-261 ° C.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₆ ClNO.HCl.0.1H ₂ O:

Theoretical: C, 71.40; H, 6.04; N, 3.09

Found: C, 71.20; H, 6.02; N, 3.00

Example 29

4- (2-Biphenyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

To a cooled (-72 ° C.) solution of t-butyllithium (1.7 M in pentane, 3.00 mL, 5.12 mmol) in tetrahydrofuran (4.0 mL) 2-bromobiphenyl in tetrahydrofuran (2 mL) (0.49 g , 2.12 mmol, 1.6 equiv) was added dropwise. The resulting solution was stirred under nitrogen atmosphere for 2 hours. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (as described in Example 5d) in tetrahydrofuran (4 mL) (0.40 g, 1.3 mmol) was added dropwise to lithiobiphenyl and the reaction was allowed to warm to room temperature over 45 minutes. Stirring was continued for 3 hours at room temperature. Excess reagent was quenched with water (10 mL) and the aqueous phase washed with ethyl acetate (2 x 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. The reaction product was purified by flash chromatography on silica gel (65 mL, eluent: 20% diethyl ether in hexane) to afford 0.43 g (72%) of the title compound as a white solid. TLC analysis (R _f 0.23, 20% diethyl ether in hexanes).

The ether solution of the free base was treated with excess etheric HCl to give hydrochloride. The solid formed was filtered, washed with clean ether and dried in vacuo (50 ° C., 10 Pascal, 18 h) to give a white solid.

mp 269-270 ° C.

Hydrochloride: Elemental Analysis for C ₃₃ H ₃₁ NO.HCl.0.75H ₂ O:

Theoretical: C, 78.09; H, 6.65; N, 2.76

Found: C, 77.98; H, 6. 49; N, 2.70

Example 30

4- (4-Biphenyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

Using the same method as in Example 29, except using 4-bromobiphenyl, the title compound was obtained in 70% yield as a white solid.

Hydrochloride: Elemental Analysis for C ₃₃ H ₃₁ NO.HCl.0.1H ₂ O:

Theoretic value: C, 79.43; H, 6.71; N, 2.89

Found: C, 79.42; H, 6.63; N, 2.79

Example 31

4- (3-Biphenyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

Using the same method as Example 29, except using 3-bromobiphenyl, the title compound was obtained as a white solid in 64% yield.

Hydrochloride: Elemental Analysis for C ₃₃ H ₃₁ NO.HCl.0.25H ₂ O:

Theoretic value: C, 79.50; H, 6.57; N, 2.81

Found: C, 79.35; H, 6. 45; N, 2.77

Example 32

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) piperidin-4-ol

To a cooled (-72 ° C.) solution of t-butyllithium (1.7 M in pentane, 5.38 mL, 9.15 mmol, 2.8 equiv) in tetrahydrofuran (24 mL) bromomethylene (0.64 mL, 4.18) under nitrogen atmosphere mmol, 1.3 equiv) was added dropwise. The metal-halogen exchange reaction was further stirred for 1 hour during which a white precipitate formed. 2-methoxypyridine (0.50 g, 4.38 mmol, 1.4 equiv) was added to this suspension and the resulting solution was allowed to warm to room temperature and then stirred at room temperature for 4 hours. The metal-added pyridine solution was again cooled to -72 ° C and 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone in tetrahydrofuran (3 mL) Example 5d) (1.00 g, 3.3 mmol) was added. The reaction was allowed to warm to room temperature over 1.5 hours. After stirring for 18 hours, further water (10 mL) was added to terminate the reaction. The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The product was purified by flash chromatography on silica gel (100 mL, eluent: 30% ethyl acetate in hexanes) to give 0.99 g (73%) of the title compound as a white solid.

TLC analysis (R _f 0.23, 30% ethyl acetate in hexanes).

The free base was dissolved in methylene chloride, diluted with ether, acidified with etheric HCl. The formed hydrochloride was filtered, washed with clean ether and dried in vacuo (50 ° C., 10 Pascal, 18 hours) to give a white solid. Got it.

mp 225-228 ° C. (decomposed).

Hydrochloride: Elemental analysis for C ₂₇ H ₂₈ N ₂ O ₂ .HCl.0.2H ₂ O:

Theoretical: C, 71.65; H, 6.55; N, 6.19

Found: C, 71.43; H, 6. 46; N, 5.84

Example 33

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-methoxy-3-pyridyl) piperidin-4-ol

The title compound was obtained in 72% yield as a white solid using a method similar to that described in Example 32 except for using 4-methoxypyridine as the starting material.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O ₂ .2HCl.1.5H ₂ O:

Theoretic value: C, 63.88; H, 6. 49; N, 5.47

Found: C, 62.92; H, 6. 20; N, 5.43

Example 34

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) piperidin-4-ol

Example, except starting with 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 1m) Using a method similar to that described in 32, the title compound was obtained in 85% yield as a white solid.

Hydrochloride: elemental analysis for C ₂₇ H ₂₇ N ₂ O ₂ Cl;

Theoretical: C, 64.64; H, 5.73; N, 5.58

Found: C, 64.66; H, 5. 66; N, 5.34

Example 35

1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) paperin-4-ol

Example 32, except that 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone is used as the starting material. Using a method similar to the above, the title compound was obtained in 36% yield as a white solid.

mp 187-189 ° C. (decomposed).

TLC analysis of organic base (R _f 0.31, 40% ethyl acetate in hexanes)

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₆ Cl ₂ N ₂ O ₂ .2HCl:

Theoretical: C, 58.50; H, 5.09; N, 5.05

Found: C, 58.24; H, 4.94; N, 4.89

Starting material piperidinone was prepared as follows:

a. Methyl 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate

Thionyl chloride (4.05 mL) in a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (Example 1j) (10.03 g, 37.1 mmol) in toluene (100 mL). , 55.7 mmol, 1.5 equiv) was added. Gas foaming was monitored with a mineral oil foaming device while the reaction was heated to reflux. After 30 minutes, gas evolution ceased, at which time the reaction was slowly cooled under nitrogen and excess methanol (10 mL) was added. The solution was heated to reflux again for 1 hour, cooled to room temperature under nitrogen and then stirred for 18 hours. Aqueous NaOH (2.5N, 60 mL) was added and the aqueous phase was extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered to give a solid. The reaction product was purified by flash chromatography on silica gel (250 mL, eluent: 15% ethyl acetate in hexanes) to give 10.2 g (97%) of the title compound as a high crystallinity white solid.

b. Methyl 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate and methyl 2-chloro-6-nitro-9,10-dihydro-9,10- Metano-9-anthracenecarboxylate

Ammonium nitrate (6.09 g, 67.8 mmol) in methyl 2-chloro-9,10-dihydro-9,10-methano-9-anthracene carboxylate (as described in Example 35a) (20.33 g, 71.4 mmol) , 0.95 equiv) was added under nitrogen. Cooled acetonitrile (0 ° C., 300 mL) was added and the suspension was homogenized within 5 minutes. Despite the presence of the ice bath, the exothermic reaction allowed the solution to warm to room temperature. After the reaction temperature had lowered, the bath was removed and the reaction was further stirred for 30 minutes. The reaction was terminated with careful use of saturated aqueous sodium bicarbonate solution (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which was a partially crystalline product. Some of the 7-nitro title compound (6.86 g) was purified from the crude reaction mixture by crystallization from hexane / ethyl acetate (twice recrystallization, 200 mL hexanes: 50 mL ethyl acetate). The remaining material, including the mother liquor obtained from crystallization, was purified by chromatography on silica gel (500 mL, eluent: 10% ethyl acetate in hexanes increased to 12% over time). These two purification steps yielded 10.83 g (46%) of the title compound and 6.59 g (28%) of the 6-nitro isomer.

c. Methyl 2-amino-7-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate

Methyl 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (as described in Example 35b) in ethanol (150 mL) (7.36 g, 22.32 mmol) To the suspension of stannous chloride dihydrate (25.2 g, 112 mmol, 5 equiv) was added. The reaction was heated to reflux, whereupon the reaction was homogenized. After heating for 2.5 hours, the solution was cooled to 0 ° C. and the reaction terminated with ice and 10% NaOH (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. The reaction product was purified by flash chromatography on silica gel (400 mL, eluent: 25% ethyl acetate in hexanes) to give 5.06 g (76%) of the title compound.

TLC analysis (R _f 0.16, 30% ethyl acetate in hexanes).

MS (CI, CH4) m / z 300 (M + 1, 100), 302 (33), 328 (M + 29, 9), 264 (12), 182 (11), 121 (11), 89 (44 )

d. Methyl 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate

To a strongly stirred solution of cupric chloride (161 mg, 1.2 mmol, 1.2 equiv) in anhydrous acetonitrile (5 mL) t-butyl nitrite (90%, 0.178 mL, 1.50 mmol, 1.5 equiv) was added under nitrogen It was. Subsequently, methyl 2-amino-7-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (as described in Example 35c) (300 mg, 1.0 mmol) was added in portions. . Gas was generated during the addition and the reaction discolored from sulfur / green to dark sulfur / brown. The addition was complete and the reaction continued to stir for 1.5 h more. 3N HCl (10 mL) was added to terminate the reaction. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (30 mL, eluent: 40% methylene chloride in hexanes) to give 230 mg (72%) of the title compound as a white solid.

TLC analysis (R _f 0.28, 40% methylene chloride in hexanes).

MS (CI, CH4) m / z 319 (M + 1, 35), 321 (24), 323 (3), 285 (20), 84 (100)

e. 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

Methyl 2.7-dichloro-9,10-dihydro-9,10-methano-9-anthracene carboxylate (as described in Example 35d) in tetrahydrofuran / methanol (1: 1 70 mL) (3.25 g, To an aqueous solution of 10.2 mmol) was added an aqueous solution of lithium hydroxide monohydrate (4.28 g, 102 mmol, 10 equiv) (35 mL). A small amount of exotherm occurred upon addition. The reaction was stirred vigorously at room temperature for 18 hours at which time a cloudy phenomenon appeared. Solvent was removed and replaced with 3N HCl (50 mL) saturated with sodium chloride. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This treatment procedure gave 3.11 g (quantitative yield) of the title compound and no further purification was necessary.

f. 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) piperidin-4-ol

A method similar to that described in Example 1k was followed except that 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (Example 35e) was used as the starting material. To give the title compound in quantitative yield as a viscous oil. No further purification or characterization was performed based on the NMR of the crude material.

g. 1- (2,7-Dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

Except 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) piperidin-4-ol (Example 35f) as starting material The title compound was obtained in 86% yield as a white solid using a method similar to that described in Example 1L.

TLC analysis (R _f 0.15, 50% ethyl acetate in hexanes).

h. 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone

Except 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol (Example 35g) as starting material The title compound was obtained in 39% yield as a white solid using a method similar to that described in Example 1m.

TLC analysis (Rf 0.18, 20% ethyl acetate in hexanes).

Example 36

4- (2-hydroxy-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

To a dimethylformamide solution (3.5 mL) of sodium hydride (60% in mineral oil, 58 mg, 1.46 mmol, 2.5 equiv) was used ethanthiol (0.108 mL, 1.46 mmol, 2.5 equiv) using a gas tight syringe under a nitrogen atmosphere. ) Was added. When gas foaming ceased, 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) in dimethyl formamide (2.0 mL) Piperidin-4-ol (as described in Example 32) (240 mg, 0.58 mmol) was added in one portion. The reaction was refluxed for 2 hours, then cooled to room temperature and diluted with water (25 mL). The precipitate formed was filtered and purified by flash chromatography on silica gel (140 mL, eluent: 15% methanol in methylene chloride) to give 190 mg (83%) of the title compound as a white solid.

The organic base was dissolved in methanol / methylene chloride, acidified with etheric HCl and diluted with ether to precipitate hydrochloride. The salt was filtered, washed with clean diethyl ether and dried in vacuo (50 ° C., 75 pascal, 18 hours) to give a white solid.

mp 195-199 ℃

Elemental Analysis for C ₂₆ H ₂₆ N ₂ O ₂ .1.9HCl:

Theoretic value: C, 66.76; H, 6.01; N, 5.99

Found: C, 66.98; H, 5. 90; N, 5.93

Example 37

4- (4-hydroxy-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-methoxy-3-pyridyl) piperidin-4-ol (as described in Example 33) The title compound was obtained in 94% yield as a white solid using a method similar to that described in Example 36, except for starting as).

Hydrochloride: Elemental Analysis for C ₂₆ H ₂₆ N ₂ O ₂ .2HCl.1.1H ₂ O:

Theoretic value: C, 63.57; H, 6. 21; N, 5.70

Found: C, 63.61; H, 6. 10; N, 5.60

Example 38

4- (6-hydroxy-2-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (6-methoxy-2-pyridyl) piperidin-4-ol (described in Example 13 The title compound was obtained in 65% yield as a white solid using a method similar to that described in Example 36, except for starting as.

Hydrochloride: Elemental Analysis for C ₂₆ H ₂₆ N ₂ O ₂ .2HCl.0.75H ₂ O:

Theoretical: C, 64.40; H, 6. 13; N, 5.78

Found: C, 64.40; H, 6. 28; N, 5.72

Example 39

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-methylamino-3-pyridyl) piperidin-4-ol

A solution of n-butyllithium (2.0 M in hexane, 7.0 mL, 14 mmol, 6.3 equiv) was added to tetrahydrofuran (25 mL) previously cooled to -72 ° C under nitrogen atmosphere. Excess methyl amine (40 mL) was condensed using another funnel with a dry ice jacket and added dropwise to the butyllithium solution. After stirring for 15 minutes, 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) piperidine-4- All hydrochloride (Example 32) (1 .00 g, 2.22 mmol) was added in one portion. The reaction was allowed to warm to room temperature and evacuated the fruit methyl amine. After refluxing the solution for 18 hours, the flask was cooled to room temperature and treated with water (25 mL). The aqueous phase was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The reaction was purified by flash chromatography on silica gel (60 mL, eluent: 40% ethyl acetate in hexanes) to give 520 mg (57%) of the title compound as a white solid.

The free base was dissolved in methylene chloride, treated with excess etheric HCl and diluted with diethyl ether to precipitate the hydrochloride. The hydrochloride was filtered, washed with clean ether and dried in vacuo (50 ° C., 10 Pascal, 18 hours) to yield an off-white solid.

mp 220-221 ° C. (decomposed).

Elemental Analysis for C ₂₇ H ₂₉ N ₃ O.2HCl.H ₂ O:

Theoretical: C, 64.54; H, 6. 62; N, 8.36

Found: C, 64.62; H, 6. 64; N, 8.12

Example 40

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-propylamino-3-pyridyl) piperidin-4-ol

The title compound was obtained in 79% yield as a white solid using a method similar to that described in Example 39, except using propyl amine.

Hydrochloride: Elemental Analysis for C ₂₉ H ₃₃ N ₃ O.0.2HCl.0.6H ₂ O:

Theoretic value: C, 66.56; H, 6.97; N, 8.03

Found: C, 66.39; H, 6.96; N, 7.66

Example 41

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-propylamino-5-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-5-pyridyl) piperidin-4-ol (Example 11) The title compound was obtained in 88% yield as a white crystalline solid using a method similar to that described in Example 39, except as starting material and using propylamine.

Hydrochloride: Elemental Analysis for C ₂₉ H ₃₃ N ₃ O.2HCl.0.25H ₂ O:

Theoretical: C, 67.37; H, 6.92; N, 8.13

Found: C, 67.35; H, 6.93; N, 8.12

Example 42

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-quinolinyl) piperidin-4-ol

To a cooled (-72 ° C.) solution of a solution of t-butyllithium (1.7 M in pentane, limited reagent, 1.90 mL, 3.19 mmol) in tetrahydrofuran (24 mL) under nitrogen atmosphere and drops ( Catalyst amount) was added dropwise. Then 2-methoxyquinoline (0.69 mL, 4.39 mmol, 1.38 equiv) was added. The reaction was stirred at −72 ° C. for 1 hour, warmed to 0 ° C. and then at this temperature for 3 hours. After cooling back to −72 ° C., 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 5d) in tetrahydrofuran (3.0 mL) (1.00 g, 3.30 mmol, 1.03 equiv) was added dropwise to the lithioquinoline solution. The reaction was stirred at rt for 18 h and the reaction terminated with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2 × 200 mL), dried over anhydrous sodium sulfate and concentrated to give an oil. The reaction mixture was purified by flash chromatography on silica gel (100 mL, eluent: 25% ethyl acetate in hexanes) to yield 1.00 g (66%) of the title compound as a white solid.

The free base was dissolved in methylene chloride, treated with etheric HCl and diluted with ether to precipitate the hydrochloride. The solid was filtered off, washed with clean diethyl ether and dried in vacuo (50 ° C., 10 Pascals, 18 hours) to give a white solid.

mp 213-217 ° C. (decomposed).

Elemental Analysis for C ₃₁ H ₃₀ N ₂ O ₂ .1.5HCl:

Theoretic value: C, 71.98; H, 6. 14; N, 5.42

Found: C, 71.78; H, 6.07; N, 5.40

Example 43

4- (2-benzothiazyl)-(9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

Except for using benzothiazole, the title compound was obtained in 65% yield as a white solid using a method similar to that described in Example 42.

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₆ N ₂ OS.2HCl.H ₂ O:

Theoretical: C, 63.51; H, 5.71; N, 5.29

Found: C, 63.26; H, 5. 38; N, 4.76

Example 44

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-pyridylmethyl) -piperidin-4-ol

The title compound was obtained in quantitative yield as a white solid using a method similar to that described in Example 42, except for using 2-picoline.

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O.2HCl.1.5H ₂ O:

Theoretical: C, 65.32; H, 6. 69; N, 5.64

Found: C, 65.34; H, 6. 46; N, 5.50

Example 45

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl) -4- (2-methoxy-3-quinolinyl) piperidin-4-ol

Example, except starting with 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 1m) The title compound was obtained in 46% yield as a white solid using a method similar to that described in 42.

Hydrochloride: Elemental Analysis for C ₃₁ H ₂₉ N ₂ O ₂ Cl.HCl.H ₂ O:

Theoretical: C, 67.51; H, 5. 84; N, 5.08

Found: C, 67.63; H, 5.51; N, 5.02

Example 46

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (4-methoxybenzyl) piperidin-4-ol

Magnesium turning (0.32 g, 1.32 mmol, 1.3 equiv) was stirred under nitrogen atmosphere for 15 minutes in the absence of solvent. Diethyl ether (20 mL) and catalytic amount of lithium iodide were added and the suspension was stirred more vigorously for 15 minutes, whereupon 4-methoxybenzyl chloride (1.08 mL, 7.0 mmol, 8 equiv) was added to the reaction flask Little by little injection. The reaction was refluxed for 3 hours to form Grignard reagent and recooled to room temperature. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) (0.30 g, 1.00 mmol) was added to a tetrahydrofuran solution ( 25 mL). After stirring for 18 hours, the reaction was terminated with water (10 mL). The aqueous phase was washed with ethyl acetate (200 mL). The organic extract was washed with water (2 × 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The reaction mixture was purified by flash chromatography on silica gel (25 mL, eluent: 20% ethyl acetate in hexanes) to give 0.29 g (69%) of the title compound as a white solid.

The free base was dissolved in methanol and methylene chloride, acidified with etheric HCl and diluted with ether to precipitate hydrochloric acid. The solid was filtered, washed with clean diethyl ether and dried in vacuo (50 ° C., 10 Pascal, 18 hours) to give a white solid.

mp 267-268 ° C. (decomposed).

Elemental Analysis for C ₂₉ H ₃₁ NO ₂ .HCl.0.7H ₂ O:

Theoretic value: C, 73.39; H, 7.09; N, 2.95

Found: C, 73.48; H, 6. 85; N, 2.85

Example 47

4- (4-Chlorobenzyl) -1- (9,10-dihydro-9,10-methanoanthracene) -9-ylmethyl) -piperidin-4-ol

In the same manner as described in Example 46, except for using 4-chlorobenzyl chloride, the title compound was obtained as a white solid (yield 86%).

Melting point 264-265 ℃

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₈ NOCl.HCl.0.1H ₂ O:

Theoretic value: C, 71.82; H, 6. 29; N, 2.99

Found: C, 71.66; H, 6. 31; N, 2.94

Example 48

4-benzyl-1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

In the same manner as described in Example 46, except for using benzyl chloride, the title compound was obtained as a white solid (yield 54%).

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₉ NO.HCl.0.3H ₂ O:

Theoretic value: C, 76.89; H, 7.05; N, 3.20

Found: C, 76.68; H, 7. 12; N, 3.21

Example 49

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (1.1-dimethylethyl) piperidin-4-ol

To a cooled solution of lithium bromide (770 mg, 8.87 mmol, 1.5 equiv) in tetrahydrofuran (60 mL) under nitrogen was added t-butyllithium (1.7 M in pentane, 4.20 mL, 7.10 mmol, 1.2 equiv) immediately after titration. Added. The resulting dark yellow color is 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 1m) in tetrahydrofuran (15 mL). Disappeared by adding a solution of (2.00 g, 5.92 mmol). The reaction was allowed to warm to room temperature for 10 minutes and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give an oil. The reaction mixture was purified by flash chromatography on silica gel (150 mL, eluent: 15% ethyl acetate in hexanes) to afford 1.22 g of the title compound as a white solid (yield 52%).

The free base was dissolved in diethyl ether containing a small amount of methylene chloride and acidified with etheric HCl. The hydrochloride was filtered off, washed with ether and dried in vacuo (60 ° C., 13 Pascal, 18 h) to give a white solid.

Melting point 294-296 ° C.

Elemental Analysis for C ₂₅ H ₃₀ ClNO.HCl.0.5H ₂ O:

Theoretic value: C, 68.02; H, 7.31; N, 3.17

Found: C, 67.96; H, 6.98; N, 3.03

Example 50

1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (1,1-dimethyl ethyl) piperidin-4-ol

Except for using 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (as described in Example 35h) as starting material In a similar manner to that described in Example 49, the title compound was obtained as a white solid (yield 51%).

Hydrochloride: Elemental Analysis for C ₂₅ H ₂₉ Cl ₂ NO.HCl:

Theoretical: C, 64.32; H, 6. 48; N, 3.00

Found: C, 64.03; H, 6. 33; N, 2.89

Example 51

4-butyl-1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

Using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material and n-butyllithium In the same manner as described in Example 49 except for the title compound was obtained as a white solid.

Hydrochloride: Elemental Analysis for C ₂₅ H ₃₁ NO.HCl.0.6H ₂ O:

Theoretical: C, 73.45; H, 8. 18; N, 3.43

Found: C, 73.09; H, 7.80; N, 4.09

Example 52

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (6-methoxy-2-benzothiazyl) piperidin-4-ol

To a cooled solution (-72 ° C.) of n-butyllithium (2.5M in hexane, 0.84 mL, 2.1 mmol, 1.05 equiv) in tetrahydrofuran (20 mL) was added as a tetrahydrofuran solution (2 mL) under nitrogen. Add methoxybenzthiazole (Reference: MD Friedman, PL Stotter, TH Porter, K. Focus, J. Med. Chem. (1973, 16. 1314) (0.36 g, 2.2 mmol, 1.1 equiv) After 40 minutes a tetrahydrofuran solution (3 mL) of 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (as described in Example 5d) The reaction was stirred for 3 hours and quenched with water (20 mL) The aqueous phase was extracted with ethyl acetate (200 mL) The organic phase was extracted with water (2 × 100 mL). ), Dried over anhydrous sodium sulfate, filtered and concentrated to give an oil The reaction mixture was on silica gel (100 mL, eluent: 30% ethyl acetate in hexane). Purification by flash chromatography gave 0.74 g of the title compound as an off-white solid (yield 72%).

The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with etheric HCl, and the hydrochloride suspension further diluted with ether. The salts were filtered off, washed with clean ether and dried under vacuum. (50 ° C, 10 Pascals, 18h) An off-white solid was obtained.

Melting point 249-251 ° C. (decomposition).

Elemental Analysis for C ₂₉ H ₂₈ N ₂ O ₂ S.2HCl.0.25H ₂ O:

Theoretical: C, 63.79; H, 5.63; N, 5.13

Found: C, 63.71; H, 5.49; N, 5.06

Example 53

4- (2-benzthienyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -piperidin-4-ol

Except for using benzthiophene, the title compound was obtained as a white solid in a similar manner to that described in Example 52 (yield 90%).

Hydrochloride: Elemental Analysis for C ₂₉ H ₂₇ NOS.HCl.0.2H ₂ O:

Theoretic value: C, 72.92; H, 5.99; N, 2.93

Found: C, 72.72; H, 5.80; N, 2.87

Example 54

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-furanyl) -piperidine-4-dhf

In the same manner as described in Example 52, except that furan was used, the title compound was obtained as an off-white solid (yield 33%),

Hydrochloride: Elemental analysis for C ₂₅ H ₂₅ NO ₂ .1.3HCl.0.2H ₂ O:

Theoretic value: C, 71.07; H, 6. 37; N, 3.12

Found: C, 70.94; H, 6. 13; N, 3.17

Example 55

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-thienyl) -piperidin-4-ol

In the same manner as described in Example 52, except that thiophene was used, the title compound was obtained as a white solid (yield 72%).

Hydrochloride: Elemental Analysis for C ₂₅ H ₂₅ NOS.1.4HCl.0.1H ₂ O:

Theoretic value: C, 68.18; H, 6.09; N, 3.18

Found: C, 67.78; H, 5.72; N, 3.14

Example 56

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-thiazyl) -piperidin-4-ol

In the same manner as described in Example 52, except that thiazole was used, the title compound was obtained as a white solid (yield 28%).

Hydrochloride: Elemental Analysis for C ₂₄ H ₂₅ N ₂ OS.2HCl.1.1H ₂ O:

Theoretical: C, 59.90; H, 5. 90; N, 5.82

Found: C, 59.52; H, 5. 64; N, 5.64

Example 57

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-thiazyl) piperidin-4-ol

2- (trimethylsilyl) thiazole and 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (as described in Example 1m) In the same manner as described in Example 52, except that was used, the title compound was obtained as a white solid (yield 40%).

Hydrochloride: Elemental Analysis for C ₂₄ H ₂₃ ClN ₂ OS.2HCl.0.5H ₂ O:

Theoretical: C, 57.09; H, 5. 19; N, 5.55

Found: C, 56.80; H, 5. 12; N, 5.37

The starting material 2- (trimethylsilyl) thiazole was prepared as follows.

a. 2- (trimethylsilyl) thiazole

2-bromothiazole (2.00 g, 12.2) in tetrahydrofuran (30 mL) to a cooled solution of n-butyllithium (2.5 M in hexane, 5.39 mL, 13.4 mmol, 1.1 equiv) in tetrahydrofuran (100 mL). mmol) was added under nitrogen. A suspension formed as substrate was added. After stirring for 30 min at −90 ° C., trimethylsilyl chloride (1.55 mL, 12.2 mmol, 1.0 equiv) immediately after distillation was added. The reaction was warmed to −30 ° C. for 1 hour and then quenched with saturated aqueous sodium bicarbonate solution (50 mL). The aqueous phase was extracted with diethyl ether (2 x 40 mL). The combined organic extracts were washed with aqueous bicarbonate (2 × 40 mL), saturated brine (1 × 40 mL) and dried over anhydrous sodium sulfate. The solvent was removed and the product was purified by kugelrohr distillation under reduced pressure (2400 Pascal, 110 ° C.). NMR analysis indicated that the title compound was contaminated with a small amount of starting material but no longer needed to be purified. The exact yield was not measured.

MS (CI, CH ₄ ) m / z 158 (M + 1, 100), 186 (M + 29, 17)

Example 58

1- (9,10-Dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) -piperidin-4-ol

To a cooled solution of distilled diisopropylamine (7.86 mL, 56.1 mmol, 1.3 equiv) in tetrahydrofuran / hexane (57 mL / 37 mL) n-butyllithium (2.5M in hexane, 23.8 mL, 59.4 mmol, 1.4 equivalents) was added under nitrogen. Protons were removed by warming the resulting solution to −20 ° C. and then recooled to −72 ° C. A yellow precipitate was then produced by dropwise addition of a tetrahydrofuran (13 mL) solution of 2-fluoropyridine (4.50 mL, 53.5 mmol, 1.25 equiv). The proton removal reaction was allowed to warm to -50 ° C for 45 minutes and to reach -30 ° C briefly before recooling to -72 ° C. To this solution 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) in tetrahydrofuran (48 mL) (13.0 g, 42.9 mmol) and lithium bromide (7.45 g, 85.8 mmol, 2 equiv) were added dropwise. The reaction was warmed to −20 ° C. for 1.5 h and then quenched with acetic acid (10 mL). The solution was diluted with water (400 mL), basified with 2.5N NaOH and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were dried over anhydrous sodium sulfate and filtered to give a solid. The product was purified by recrystallization from ethyl acetate (3 crops) to give 13.3 g of the title compound as a white solid (yield 77%).

The free base was dissolved in ether and acidified with etheric HCl. The hydrochloride was filtered off, washed with ether and dried under vacuum (room temperature, 10 Pascal, 18 hours) to give a white solid.

Melting Point 188-191 ° C (Decomposition)

Elemental Analysis for C ₂₆ H ₂₅ FN ₂ O.HCl.0.4H ₂ O:

Theoretical: C, 70.31; H, 6.08; N, 6.31

Found: C, 70.65; H, 6. 12; N, 5.83

Example 59

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridylmethyl) -piperidin-4-ol

The title compound was obtained as a white solid in a similar manner to that described in Example 58 except that 3-picoline was used (yield 46%).

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O.2HCl.1.5H ₂ O:

Theoretical: C, 65.32; H, 6. 70; N, 5.64

Found: C, 65.31; H, 6.59; N, 5.31

Example 60

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylthio-3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) piperidine- in tetrahydrofuran (50 mL) To a 4-ol (described in Example 58) (2.00 g, 5.00 mmol, 1 equiv) solution was added sodium salt of ethanethiol (0.90 g, 10.7 mmol, 2.2 equiv) under nitrogen. Thiolate salts were prepared from ethanethiol and sodium hydride under standard conditions. The reaction was heated at reflux for 18 hours and quenched by pouring water (100 mL). The aqueous phase was extracted with diethyl ether (2 x 100 mL). The combined organic extracts were washed with water (2 × 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (200 mL, eluent: 50% ether in hexanes) to afford 2.00 g of the title compound (yield 90%).

The free base was dissolved in ether and acidified with etheric HCl. The hydrochloride was filtered, washed with ether and dried under vacuum (room temperature, 10 Pascal, 18 hours) to give a white solid.

Melting point 176-179 ° C. (decomposition).

Elemental Analysis for C ₂₈ H ₃₀ N ₂ OS.2HCl.0.5H ₂ O:

Theoretical: C, 64.11; H, 6. 34; N, 5.34

Found: C, 64.05; H, 6. 32; N, 5.26

Example 61

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-propyloxy-3-pyridyl) piperidin-4-ol

In the same manner as described in Example 60, except that n-propanol was used, the title compound was obtained as a white solid (yield 86%).

Hydrochloride: Elemental Analysis for C ₂₉ H ₃₂ N ₂ O ₂ .2HCl.0.5H ₂ O:

Theoretical: C, 66.66; H, 6.75; N, 5.36

Found: C, 67.76; H, 6.59; N, 5.16

Example 62

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (2,2,2-trifluoroethoxy) -3-pyridyl) piperi Din-4-ol

In the same manner as described in Example 60, except that 2,2,2-trifluoroethanol was used, the title compound was obtained as a white solid (yield 94%).

Hydrochloride: Elemental Analysis for C ₂₈ H ₂₇ N ₂ O ₂ F ₃ .1.5HCl:

Theoretical: C, 62.84; H, 5. 37; N, 5.23

Found: C, 62.98; H, 5.40; N, 5.20

Example 63

4- (2-benzyloxy-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

In the same manner as described in Example 60, except that benzyl alcohol was used, the title compound was obtained as a white solid (yield 94%).

Hydrochloride: Elemental Analysis for C ₃₃ H ₃₂ N ₂ O ₂ .2HCl.H ₂ O:

Theoretic value: C, 68.39; H, 6. 26; N, 4.83

Found: C, 68.30; H, 6.00; N, 4.97

Example 64

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methoxy-3-pyridyl) piperidin-4-ol

In the same manner as described in Example 60, except that methanol was used, the title compound was obtained as a white solid (yield 94%).

Hydrochloride: Elemental analysis for C ₂₇ H ₂₈ N ₂ O ₂ .HCl.0.2H ₂ O:

Theoretical: C, 71.65; H, 6.55; N, 6.19

Found: C, 71.43; H, 6. 46; N, 5.84

Example 65

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (1-methylethoxy) -3-pyridyl) piperidin-4-ol

In the same manner as described in Example 60, except that 2-propanol was used, the title compound was obtained as a white solid (quantitative yield).

Hydrochloride: Elemental Analysis for C ₂₉ H ₃₂ N ₂ O ₂ .2.3HCl.H ₂ O:

Theoretical: C, 64.20; H, 6. 74; N, 5.16

Found: C, 64.55; H, 6. 27; N, 4.71

Example 66

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (N-pyrrolidinyl) -3-pyridyl) piperidin-4-ol

To a cooled solution (0 ° C.) of pyrrolidine (0.417 mL, 5.00 mmol, 5 equiv) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexane, 1.92 mL, 4.80 mmol, 4.8 equiv). Add under nitrogen. Then 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) piperidine in tetrahydrofuran (10 mL) 4-ol (as described in Example 58) was added. The bath was removed and the solution was allowed to warm to room temperature for 1.5 hours. There was no obvious reaction after stirring for 18 hours. To promote the reaction 18-crown-6 (0.528 g, 2.00 mmol, 2.0 equiv) was added and the solution was heated to 60 ° C. for 5 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography on silica gel (35 mL, eluent: 50% ethyl acetate in hexanes) to afford 0.450 g (quantitative yield) of the title compound.

The free base was dissolved in ether and acidified with etheric HCl. The hydrochloride was filtered, washed with clean ether and dried under vacuum (60 ° C., 16 Pascal, 18 hours) to give a white solid.

Melting point 249-253 ° C.

Elemental Analysis for C ₃₀ H ₃₃ N ₂ O.2HCl.H ₂ O:

Theoretical: C, 66.60; H, 6. 86; N, 7.77

Found: C, 66.78; H, 6. 66; N, 7.64

Example 67

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (N-methylethylamino) -3-pyridyl) piperidin-4-ol

In the same manner as described in Example 66, except that N-methyl-ethylamine was used, the title compound was obtained as a white solid (yield 59%).

Hydrochloride: Elemental Analysis for C ₂₉ H ₃₃ N ₃ O.2.5HCl.0.5H ₂ O:

Theoretic value: C, 64.53; H, 6. 82; N, 7.78

Found: C, 64.71; H, 6.95; N, 7.44

Example 68

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (N-methylamino) -3-pyridyl) piperidin-4-ol

In the same manner as described in Example 66, except that methylamine was used, the title compound was obtained as a white solid (yield 89%).

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₉ N ₃ O.2HCl.H ₂ O:

Theoretical: C, 64.54; H, 6. 62; N, 8.36

Found: C, 64.62; H, 6. 64; N, 8.12

Example 69

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-hydroxymethyl) -3-pyridyl) piperidin-4-ol

4- (5- (t-butyldimethylsilyl) oxymethyl-3-pyridyl) -1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperi A tetrahydrofuran solution (15 mL) of din-4-ol (1.70 g, 3.04 mmol) was cooled to 0 ° C. under nitrogen and tetrabutylammonium fluoride (1.0 N in tetrahydrofuran, 3.20 mL, 3.20 mmol, 1.05 equiv. ). The reaction was warmed to rt and the resulting aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. This procedure gave 1.20 g (89%) of the title compound.

The free base was dissolved in ether and acidified with etheric HCl. The hydrochloride was filtered, washed with clean ether and dried under vacuum (room temperature, 10 Pascal, 10 hours) to give a white solid.

Melting point 235-240 ° C. (decomposition).

Elemental Analysis for C ₂₇ H ₂₇ N ₂ O ₂ Cl.2HCl.0.7H ₂ O:

Theoretical: C, 60.55; H, 6. 23; N, 5.23

Found: C, 60.26; H, 5.71; N, 5.13

The silyl ether starting material was prepared as follows.

a. 3-bromo-5- (hydroxymethyl) pyridine

Thionyl chloride (6.00 mL, 81.7 mmol, 1.1 equiv) was added to a toluene suspension of 5-bromonicontinic acid (15.00 g, 74.3 mmol). The suspension was heated to reflux and gas foaming was monitored with a mineral oil foaming device. After 60 minutes the system was homogenized and reached steady state for gas foaming. Excess thionyl chloride and solvent were removed in vacuo to give the hydrochloride salt of solid acid chloride. In a separate flask sodium borohydride (9.10 g, 241 mmol, 13 equiv) was added to anhydrous ethanol and cooled to -10 ° C under nitrogen. Acid chloride was added in portions for 20 minutes and the reaction temperature was kept at 0 ° C at all times. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 hour. Water (200 mL) was added and the aqueous phase extracted with diethyl ether (2 × 200 mL). The combined organic extracts were washed with water (100 mL), dried over anhydrous potassium carbonate and filtered. The product was precipitated in hydrochloride form by treating the solution with ethereal HCl. The solid was dried under vacuum (at room temperature. 16 pascals, 7 hours). No further purification was necessary. The recovery amount of the title compound hydrochloride was 10.04 g (yield 60%).

MS (CI, CH4) m / z 188 (M + 1,100), 190 (99), 216 (M + 29, 8), 218 (8), 170 (25), 172 (24)

b. 3-bromo-5- (t-butyldimethylsilyl) oxymethylpyridine

Triethylamine (2.50 mL, 17.9 mmol, 4 equiv) in a methylene chloride solution (20 mL) of 3-bromo-5- (hydroxymethyl) pyridine hydrochloride (as described in Example 69a) (1.00 g, 4.48 mmol) And t-butyl dimethylsilylchloride (0.75 g, 5.0 mmol, 1.1 equiv) were added under nitrogen. The resulting solution was heated to reflux for 18 hours to room temperature and diluted with diethyl ether (200 mL). The organic phase was washed with 2.5N NaOH (1 × 100 mL), water (3 × 100 mL) and saturated brine (1 × 100 mL). The ether solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give a colorless oil. The yield of the title compound produced was 1.10 g (yield 81%). No further purification was necessary.

TLC analysis (R _f 0.19, ethyl acetate)

MS (CI, CH4) m / z 302 (M + 1,100), 304 (96), 330 (M + 29, 4), 332 (4)

c. 4- (5-t-butyldimethylsilyl) oxymethyl-3-pyridyl) -1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidine -4-ol

3-bromo-5- (t-butyldimethylsilyl) oxymethylpyridine (as described in Example 69b) and 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9- The title compound was obtained as an oil (yield 51%) in a similar manner as described in Example 1, except that ylmethyl) piperidinone (described in Example 1m) was used.

Example 70

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (hydroxymethyl) -3-pyridine) piperidin-4-ol

4- (5- (t-butyldimethylsilyl) oxymethyl-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidine-4- In the same manner as described in Example 69, except that Ol was used as the starting material, the title compound was obtained as a white solid (yield 85%).

Hydrochloride: Elemental Analysis for C ₂₇ H ₂₈ N ₂ O ₂ .2HCl.0.9H ₂ O:

Theoretical: C, 64.64; H, 6.39; N, 5.58

Found: C, 64.50; H, 6. 34; N, 5.48

The starting material silflf was prepared as follows.

a. 4- (5-(-butyldimethylsilyl) oxymethyl-3-pyridyl) -1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 5d) was used as starting material and 3-bromo-5- (t- The title compound was obtained as an oil in a similar manner as described in Example 1 except for using butyldimethylsilyl) oxymethylpyridine (Example 69b) (yield 62%).

Example 71

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (hydroxymethyl) -5-thiazyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (2- (t-butyldimethylsiloxymethyl) thiazyl) piperidine-4- The title compound was obtained as a white solid in a similar manner as described in Example 69, except that Ol was used as the starting material (yield 48%).

The starting material, silyl ether, was prepared as follows.

a. 2-formylthiazole

To a cooled solution (-95 ° C.) of t-butyllithium (1.7 M in pentane, 17.9 mL, 30.5 mmol, 2.0 equiv) in tetrahydrofuran (150 mL) was added 2-bromothiazole (2.50 g, 15.3 mmol). Add under nitrogen. The resulting suspension was stirred at −80 ° C. or below for 45 minutes. The lithiated thiazole solution was transferred via cannula at −90 ° C. to a solution of dimethylformamide (1.42 mL) in tetrahydrofuran (100 mL). The reaction was warmed to room temperature for 2 hours and quenched by addition of water (100 mL).

The aqueous phase was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give crude oil (yield 87%).

TLC analysis (R _f 0.50, 40% ethyl acetate in hexanes). No further characterization was performed. The crude title compound was reduced with sodium borohydride.

b. 2- (hydroxymethyl) thiazole

To a cooled solution (0 ° C.) of 2-formylthiazole (described in Example 71a) in methanol (25 mL) was added sodium borohydride (0.300 g, 7.94 mmol) under nitrogen. After the addition was complete, the reaction was warmed to room temperature for 1 hour and stirred at room temperature for 3 hours. Excess reagent was quenched with acetone (10 mL) and stirred for 18 h. The reaction was acidified with 3N HCl (25 mL), cooled to 0 ° C. and rebasicated with 2.5N NaOH (40 mL). The aqueous phase was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a relatively pure oil (yield 62%).

TLC analysis results (R _f 0.15, 40% ethyl acetate in hexanes). No further purification was necessary.

MS (CI, CH ₄ ) m / z 116 (M + 1, 80), 144 (M + 29, 17), 98 (100)

c. 2- (t-butyldimethylsilyl) oxymethylthiazole

The title compound was obtained (yield 92%) in a similar manner as described in Example 69b, except that 2- (hydroxymethyl) thiazole (described in Example 71b) was used as starting material.

TLC analysis result (R _f 0.21, 10% ether in hexanes).

MS (CI, CH 4) m / z 230 (M + 1, 26), 258 (M + 29, 11), 214 (24), 172 (100).

d. 4- (2- (t-butyldimethylsilyl) oxymethyl-5-thiazyl) -1- (9,10-dihydro-methanoanthracene-9-ylmethyl) piperidin-4-ol

2- (t-butyldimethyl) using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material The title compound was obtained as a yellow oil in a similar manner as described in Example 69 except for using silyl) oxymethylthiazole (as described in Example 71c) (yield 58%).

TLC analysis (R _f 0.19, 25% ethyl acetate in hexanes).

MS (CI, CH ₄ ) m / z 533 (M + l, 100), 561 (M + 29, 16), 515 (21), 475 (12).

Example 72

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-N-methylcarbamoylmethyl-3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-hydroxymethyl-3-pyridyl) piperidine-4 in methylene chloride (5 mL) To the -ol (described in Example 70) (0.50 g, 1.12 mmol) solution was added methyl isocyanate (0.070 mL, 1.18 mmol, 1.05 equiv) and N-methylpiperidine (0.10 mL, 0.82 mmol, 0.75 mmol) It was. The resulting solution was heated at reflux for 9 hours, cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The reaction product was purified by flash chromatography on silica gel (60 mL, eluent: 75% ethyl acetate in hexane) to give 0.380 g of the title compound as a white solid (yield 67%).

The organic base was dissolved in ether containing methylene chloride and acidified with etheric HCl. The hydrochloride was charged by dilution with ether, filtered and dried under vacuum (room temperature, 10 Pascal, 18 hours) to give a white solid.

Example 73

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (1-hydroxyethyl) -3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-formyl-3-pyridyl) piperidine-4 in tetrahydrofuran (20 mL) A suspension of -ol (0.350 g, 0.852 mmol) was cooled to 0 ° C. under nitrogen. Methyl lithium (1.0 M in diethyl ether, 1.72 mL, 2 equiv) was added dropwise and the suspension dissolved while addition. The solution turned golden brown. The reaction was warmed to 10 ° C. and stirred at this temperature for 2.5 hours. At the end of the stirring period the reaction was quenched with water (25 mL) and the aqueous phase extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were purified by flash chromatography on silica gel (30 mL, eluent: 10% methanol in diethyl ether) to yield 0.280 g of the title compound as a white solid (yield 77%).

The free base was dissolved in methylene chloride containing a small amount of methanol and acidified with ethereal HCl. The hydrochloride was diluted with ether, charged, filtered, washed with ether and dried under vacuum (60 ° C., 10 Pascal, 18 hours) to obtain a white solid.

mp 177-183 ℃

The results of elemental analysis of the dihydrochloride salt are different from the theoretical ones.

1 H NMR and MS of the salt were completely consistent with the proposed structure

The starting material pyridine aldehyde derivative was prepared as follows.

a. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5-formyl-3-pyridyl) piperidin-4-ol

Dimethyl sulfoxide (0.971 mL, 13.68 mmol, 4 equivalents) immediately after distillation into a cooled solution (-78 ° C.) of oxalyl chloride (0.597 mL, 6.84 mmol, 24 equivalents) in methylene chloride (15 mL) was removed under nitrogen. Added. After 10 minutes 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (hydroxy methyl) -3-pyridyl as dimethylsulfoxide solution (15 mL) Piperidin-4-ol (as described in Example 70) (1.41 g, 3.42 mmol) was added. The reaction was stirred for 1 h at -78 &lt; 0 &gt; C, then triethylamine (3.81 mL, 27.4 mmol, 8 equiv) was added. The cooling bath was removed and the reaction warmed for 2 hours. The reaction was quenched by addition of water (35 mL) and the product extracted with methylene chloride (3 × 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid. The reaction product was purified by flash chromatography on silica gel (65 mL, eluent: 10% hexane in ethyl acetate) to give 1.04 g of the title compound (yield 74%).

Example 74

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (methoxycarbonyl) -3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (4-methyl-2,6,7-trioxabicyclo [] in methanol (5 mL) 2.2.2] To a heterogeneous solution of oct-1-yl) -3-pyridyl) piperidin-4-ol (0.97 g, 1.90 mmol) was added sulfuric acid (0.21 mL, 2 equiv) under nitrogen. The acid was added and the suspension dissolved. The reaction was stirred for 24 hours and basified with 2.5N NaOH (25 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. Purification of the reaction product by flash chromatography on silica gel (65 mL eluent: 20% hexane in ethyl acetate) afforded 0.560 g of the title compound as a white solid (yield 67%).

The organic base was dissolved in ether containing methylene chloride and acidified with etheric HCl. Dilution with ether gave the hydrochloride salt, filtered, washed with clean ether and dried in vacuo (60 ° C., 10 Pascal, 18 hours) to give a white solid.

mp 243-247 ° C. (decomposition).

Elemental Analysis for C ₂₈ H ₂₈ N ₂ O ₃ .2HCl.H ₂ O:

Theoretic value: C, 63.28; H, 6.07; N, 5.27

Found: C, 63.24; H, 5. 90; N, 5.03

The starting material, orthoester, was prepared as follows.

a. 3-methyl-3-oxetanemethyl-5-bromonicotinate

Thionyl chloride (2.0 mL, 27.4 mmol, 1.1 equiv) was added to a toluene suspension (50 mL) of 5-bromonicotinic acid (5.02 g, 24.9 mmol). The suspension was heated to reflux and gas foaming was monitored with a mineral foaming device. After 45 minutes the system was homogenized and reached steady state for gas bubbles. The reaction was cooled to room temperature. Excess thionyl chloride and solvent were removed in vacuo and replaced with methylene chloride (50 mL). Oxetane methanol (2.73 mL, 24.7 mmol, 1.1 equiv) was added followed by triethylamine (8.70 mL, 62.3 mmol, 2.5 equiv). A significant amount of precipitate formed as the reaction was stirred at room temperature under nitrogen. After 24 hours the excess reagent was quenched with water (40 mL) and the aqueous phase was extracted with methylene chloride (2 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (250 mL, eluent: 20% ethyl acetate in hexanes) to give 5.10 g of the title compound as a high crystalline white solid (72% yield).

TLC analysis result (R _f 0.15, 20% ethyl acetate in hexanes).

MS (CI, CH ₄ ) m / s 286 (M + l, 100), 288 (99), 314 (M + 29, 15), 316 (15).

b. 3-bromo-5- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octyl) pyridine

A methylene chloride solution of 3-methyl-3-oxetanemethyl-5-bromonicotinate (as described in Example 74a) (2.50 g, 8.73 mmol) was cooled to 0 ° C. under nitrogen. Boron trifluoride etherate (1.34 mL, 10.9 mmol, 1.25 equiv) was added and the resulting solution was stirred at 0 ° C. for 25 h. The amine salt was precipitated by quenching the reaction with excess triethyl amine and diethyl ether dilution. Baseline impurities were removed by filtration on silica gel (20 g, pretreated with 1% triethylamine in ether). The reaction product was purified by flash chromatography on silica gel (150 mL, eluent: 15% ethyl acetate in hexane) to give 2.02 g of the title compound as colorless oil (yield 81%).

TLC analysis results (R _f 0.29 20% ethyl acetate in 1% triethylamine).

MS (CI, CH ₄ ) m / z 286 (M + l, 100), 288 (99), 222 (19), 314 (M + 29, 19), 316 (19).

c. 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (4-methyl-2,6-7-trioxabicyclo [2.2.2]- 1-octyl) -3-pyridyl) piperidin-4-ol

3-bromo-5- using 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (described in Example 5d) as starting material White solid, in a similar manner as described in Example 1, except that (4-methyl-2,6,7-trioxabicyclo [2.2.2] octyl) pyridine (as described in Example 74b) was used. As the title compound (yield 75%).

TLC analysis result (R _f 0.25, 20% hexanes in ethyl acetate).

MS (CI, CH ₄ ) m / z 511 (M + l, 100), 539 (M + 29, 16), 493 (16).

Example 75

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (N-propylcarboxamido) -3-pyridyl) piperidine-4- Come

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (5- (methoxycarbonyl) -3-pyridyl) piperi in propylamine (5 mL) A solution of din-4-ol (as described in Example 74) (0.560 g, 1.27 mmol) was heated at reflux under nitrogen for 68 hours. The oil was obtained by removing the solvent in vacuo. The crude reaction product was purified by flash chromatography on silica gel (35 mL, eluent: ethyl acetate) to give 0.450 g of the title compound (yield 76%).

The salts were charged by dissolving the free base in methanol, acidifying with etheric HCl and then diluting with ether. The hydrochloride was filtered off, washed with ether and dried under vacuum (60 ° C., 10 Pascal, 18 hours) to obtain a white solid.

mp 205-208 ° C.

Elemental Analysis for C ₃₀ H ₃₃ N ₃ O ₂ .2HCl.0.4H ₂ O:

Theoretic value: C, 65.79; H, 6.59; N, 7.67

Found: C, 65.70; H, 6. 64; N, 7.47

Example 76

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N, N-dimethylsulfamoylphenyl) piperidin-4-ol

N-butyllithium (1.21 mL of 2.29 M solution in hexanes, 2.77 mmol) in tetrahydrofuran (10 mL) was cooled to −38 ° C. and N, N-dimethylbenzenesulfonamide (510 mg) in tetrahydrofuran (5 mL). , 2.277 mmol) solution. The mixture was warmed to 0 ° C. and stirred for 20 minutes, then cooled to −30 ° C. and then 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl in tetrahydrofuran (5 mL). ) -4-piperidinone (as described in Example 5d) solution. The mixture was allowed to warm to room temperature, stirred for 0.5 h and then poured into 1N aqueous sodium hydroxide solution. The mixture was extracted with chloroform (3 × 50 mL). The organic extracts were washed with brine (50 mL), combined, dried over anhydrous potassium carbonate, filtered and evaporated to give a tan foam (1.3 g). White powder (502 mg) was obtained by purification by flash chromatography (eluent: 6: 1-3: 1 hexane / acetone). This solid was dissolved in diethyl ether and treated with ethereal HCl to give the hydrochloride (486 mg, 0.92 mmol, 40%) of the title compound as a white powder.

mp 220-223 ° C.

Elemental Analysis for C ₂₉ H ₃₂ N ₂ O ₃ .HCl.0.25H ₂ O:

Theoretic value: C, 65.77; H, 6. 38; N, 5.29

Found: C, 65.92; H, 6. 35; N, 5.12

Example 77

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-methylsulfamoylphenyl) piperidin-4-ol

The title compound was obtained as a white solid in a manner similar to that described in Example 76, except that N-methylbenzenesulfonamide was used in the direct lithiation reaction step (yield 42%).

mp 179-182 ° C.

Elemental Analysis for C ₂₈ H ₃₀ N ₂ O ₃ S:

Theoretic value: C, 70.86; H, 6. 37; N, 5.90

Found: C, 60.73; H, 6. 42; N, 5.89

Example 78

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N, N-dimethylsulfamoyl-5-methoxyphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner as described in Example 76, except that N, M-dimethyl-4-methoxybenzenesulfonamide was used in the direct lithiation reaction step (yield 26%).

mp 101-103 ° C.

Elemental Analysis for C ₃₀ H ₃₄ N ₂ O ₄ S:

Theoretic value: C, 69.42; H, 6. 61; N, 5.40

Found: C, 69.25; H, 6. 48; N, 5.30

Example 79

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-2- (N-methylsulfamoyl-5-methoxyphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner as described in Example 76, except that N-methyl-4-methoxybenzenesulfonamide was used for the direct lithiation reaction step (yield 23%).

mp 209-211 ℃

Elemental Analysis for C ₂₉ H ₃₂ N ₂ O ₄ S:

Theoretic value: C, 69.02; H, 6.39; N, 5.55

Found: C, 69.08; H, 6. 43; N, 5.46

Example 80

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-propylsulfamoyl-5-methoxyphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner as described in Example 76, except that N-propyl-4-methoxybenzenesulfonamide was used in the direct lithiation reaction step (yield 34%).

mp 169-170 ° C.

Elemental Analysis for C ₃₁ H ₃₆ N ₂ O ₄ S:

Theoretical: C, 69.90; H, 6.81; N, 5.26

Found: C, 69.79; H, 6.92; N, 5.29

Example 81

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-propylsulfamoylphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner as described in Example 76, except that N-propylbenzenesulfonamide was used in the direct lithiation reaction step (yield 54%).

mp 131-133 ° C.

Elemental analysis for C ₃₀ H ₃₄ N ₂ O ₃ S.0.25 H ₂ O:

Theoretical: C, 71.04; H, 6. 85; N, 5.52

Found: C, 71.03; H, 6. 82; N, 5.69

Example 82

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-pyrrolidinylsulfamoylphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner to that described in Example 76 except that pyrrolidinyl benzenesulfonamide was used in the direct lithiation reaction step (yield 15%).

mp 203-204 ° C.

Elemental Analysis for C ₃₁ H ₃₄ N ₂ O ₃ :

Theoretic value: C, 72.34; H, 6. 66; N, 5.44

Found: C, 72.22; H, 6. 72; N, 5.41

Example 83

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-ethylsulfamoylphenyl) piperidin-4-ol

The title compound was obtained as a white powder in a similar manner as described in Example 76, except that N-ethylbenzenesulfonamide was used in the direct lithiation reaction step (yield 52%).

mp 184-185 ° C.

Elemental analysis for C ₂₉ H ₃₂ N ₂ O ₃ S.0.2H ₂ O:

Theoretic value: C, 71.28; H, 6. 60; N, 5.73

Found: C, 70.90; H, 6. 66; N, 5.79

Example 84

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-methylsulfamoyl-5-methoxyphenyl) piperidine-4 -All

N-methyl-4-methoxybenzenesulfonamide was used in the direct lithiation step and 1- (2-chloro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example Using the same method as described in Example 76, except that 1 m) was used, the title compound was obtained as a white powder (29%).

mp 179-182 ° C.

Elemental Analysis for C ₂₉ H ₃₁ ClN ₂ O ₃ S:

Theoretical: C, 64.61; H, 5.79; N, 5.19

Found: C, 64.30; H, 5. 90; N, 5.18

Example 85

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N, N-dimethylsulfamoyl-5-methoxyphenyl) piperidine -4-ol

In the direct lithiation reaction step, N, N-dimethyl-4-methoxybenzenesulfonamide was used and 1- (2-chloro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone ( Using the method analogous to that described in Example 76, except that Example 1m) was used, the title compound was obtained as a white powder (27%).

mp 190-191 ° C.

Elemental Analysis for C ₃₀ H ₃₃ ClN ₂ O ₄ S:

Theoretical: C, 65.15; H, 6.01; N, 5.06

Found: C, 64.86; H, 5.98; N, 4.80

Example 86

1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-N-methylsulfamoyl-5-methoxyphenyl Piperidine-4-ol

In the direct lithiation reaction step using N-methyl-4-methoxybenzenesulfonamide, 1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9 The title compound was obtained (44%) as a white powder using a method similar to that described in Example 76, except for using -ylmethyl) -4-piperidinone.

mp 140-142 ° C.

Elemental Analysis for C ₂₉ H ₃₁ ClN ₂ O ₄ S:

Theoretical: C, 64.18; H, 5.83; N, 5.16

Found: C, 64.14; H, 5.94; N, 4.19

Example 87

1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol

1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol (280 mg, 0.602 mmol) of tetrahydrofuran solution (10 mL) was added boron trifluoride etherate (0.306 mL, 2.41 mmol, 4 equiv) and boron dimethyl sulfide complex (10 M, 0.250 mL, 4 equiv) under nitrogen atmosphere. The reaction was then heated to reflux for 24 hours. Thereafter, a solution of methanol and 3N HCl (25 mL, 1: 1 volume ratio) was added and then refluxed for 20 minutes. The reaction was cooled to rt and basified with 2.5N NaOH (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography on silica gel (30 mL, eluent: ethyl acetate) to give 190 mg (70%) of off-white foam.

The free base was dissolved in methanol / methylene chloride, acidified with etheric HCl and diluted with ether to charge the hydrochloride. The hydrochloride was filtered, washed with clean ether and dried in vacuo (60 ° C., 10 Pascal, 18 hours) to give a white solid.

mp 252-254 ° C. (decomposed).

Elemental Analysis for C ₂₆ H ₂₅ Cl ₂ N ₂ O.2.1HCl.2H ₂ O:

Theoretical: C, 55.37; H, 5. 38; N, 4.97

Found: C, 55.26; H, 4.96; N, 4.70

The starting material amide was prepared as follows.

a. 1- (2,7-dichloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol

Toluene solution (10 mL) of 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 35e) (0.363 g, 1.19 mmol) Onyl chloride (0.087 mL, 1.2 mmol, 1 equiv) was added. Gas foaming was monitored by the mineral oil foaming device while the reaction was heated to reflux for 2 hours. Toluene was removed and replaced with clean toluene and stripped to dryness. This procedure was repeated twice. The residue was dissolved in tetrahydrofuran (10 mL). Triethylamine (0.17 mL, 1.2 mmol, 1 equiv) and 4-hydroxy-4- (3-pyridyl) piperidine (0.212 g, 1.2 mmol, 1 equiv) were added to this solution. The tetrahydrofuran solution was heated to reflux for 18 hours, cooled to room temperature and poured into ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (50 mL, eluent: 10% methanol in methylene chloride increased to 20%) to afford 0.29 g (52%) of a white solid.

The starting material pyridylpiperidine was prepared as follows.

b. 1- (carbenzyloxy) piperidin-4-ol

A solution of 4-hydroxypiperidine (25.0 g, 0.247 moles) in methylene chloride (2000 mL) was cooled to 0 ° C. with stirring at the top under nitrogen. Triethylamine (86.1 mL, 0.618 moles, 2.5 equiv) was added followed by benzyl chloroformate (35.3 mL, 0.247 moles, 1.0 equiv). The reaction was allowed to warm to room temperature over 1 hour and held at this temperature for 5 hours. A significant amount of amine hydrochloride precipitated during the treatment. The organic phase was washed with 3N HCl (3 × 250 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give 47.0 g (81%) of the title compound as an oil. This product was subjected to Swern oxidation without any further purification.

TLC analysis results (R _f 0.17, 50% ethyl acetate in hexanes).

MS (CI, CH4) m / z 236 (M + 1, 42), 218 (4), 192 (10), 181 (9), 174 (15), 91 (100)

c.1-carbenzyloxy-4-piperidone

Dimethyl sulfoxide (29.6 mL, 0.42 moles, 3.0 equivalents) immediately after distillation in oxalyl chloride (18.2 mL, 0.21 moles, 1.5 equivalents) in chilled (-78 ° C.) solution in methylene chloride (1400 mL) ) Was added. After stirring the solution for 10 minutes, methylene chloride solution (150 mL) of 1-carbenzyloxypiperidin-4-ol (as described in Example 87b) (32.76 g, 0.139 mmol) was cannulated. Added. The solution was left at -78 ° C for 30 minutes. Triethylamine (116 mL, 0.83 mole, 6.0 equiv) was added and the reaction was allowed to warm to room temperature over 1.5 h. Once room temperature was reached, the reaction was terminated with 3N HCl (400 mL). The organic phase was washed with 3N HCl (2 × 400 mL), 2.5N NaOH (2 × 400 mL) and saturated brine (1 × 400 mL). The methylene chloride phase was dried over anhydrous magnesium sulfate, filtered over 100 g of silica gel and concentrated to give an oil. This treatment yielded 23.8 g (73%) of the title compound, which was no longer purified.

d. 1-carbobenzyloxy-4- (3-pyridyl) piperidin-4-ol

To a low temperature (-78 ° C) solution of n-butyllithium (2.0 M in hexane, 12.9 mL, 28.3 mmol, 1.2 equiv) in tetrahydrofuran (200 mL) under 3-nitromopyridine (2.27 mL, 23.6 mmol, 1.1 equiv) was added. The solution turned dark green with the addition of pyridine. The reaction was stirred at this temperature for 1 hour, at which time 1-carbobenzyloxy-4-piperidone (described in Example 87c) (5.00 g, 21.4 mmol) was added as a tetrahydrofuran solution (20 mL). It was. The cold bath was removed and the reaction was allowed to warm to room temperature and stirred at this temperature for 18 hours. The reaction was terminated by addition of water (125 mL) and the aqueous phase extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (300 mL, eluent: ethyl acetate) to give 5.00 g (75%) of the title compound as an oil.

e. 4- (3-pyridyl) piperidin-4-ol

10% palladium / carbon in a solution of 1-carbenzyloxy-4- (3-pyridyl) piperidin-4-ol (described in Example 87d) (3.17 g, 10.2 mmol) in ethanol (100 mL) (2.0 g) was added. Excess cyclohexene (50 mL) was then added. The reaction was refluxed for 2 hours under nitrogen. The suspension was cooled and filtered and the catalyst washed with clean ethanol. The filtrate was concentrated in vacuo to yield 1.70 g (94%) of an off-white solid, which was no longer purified.

Examples 88,90 and 91 describe a specific reaction procedure for preparing compounds of formula (I) wherein X and Y are halo and hydroxy, wherein the compound is a 2-halo-7-alkoxy derivative It is a precursor compound for preparing the compound of formula (I).

Example 88

1- (2-chloro-7-nitro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol

Starting material 1- (2-chloro-7-nitro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol Using the method analogous to that described in Example 87, except for using the above, the title compound was obtained in 84% yield as a white solid.

The starting material amide was prepared as follows.

a. 2-Chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

Example, except using methyl 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (as described in Example 35b) as starting material Using the method similar to that described in 35e, the title compound was obtained in quantitative yield. No characterization was performed prior to subsequent reactions.

b. 1- (2-chloro-7-nitro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol

Example 87a, except that 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 89a) is used as starting material Using a method similar to that described in, the title compound was obtained in 59% yield as off-white foam.

TLC analysis (R _f 0.20, ethyl acetate).

MS (CI, CH 4) m / z 476 (M + l, 100), 478 (33), 504 (M + 29, 21), 446 (25), 458 (30).

Example 89

1- (2-amino-7-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol

1- (2-amino-7-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol Using the method analogous to that described in Example 87, except that it was used as the material, the title compound was obtained in 88% yield as an off-white solid.

The starting material amide was prepared as follows.

a. 2-Amino-7-chloro-9, 10-dihydro-9, 10-methano-9-anthracenecarboxylic acid

Example 35e, except that 2-amino-7-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in Example 35c) is used as starting material Using a method similar to that described in, the title compound was obtained in 51% yield as off-white solid.

TLC analysis (R _f 0.23, 20% ethyl acetate in hexanes).

MS (CI, CH 4) m / z 300 (M + l, 100), 302 (37), 328 (M + 29, 17), 264 (36), 227 (91), 201 (55).

Example 90

1- (2-Chloro-7-hydroxy-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol

1- (2-chloro-7-hydroxy-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol Using the method analogous to that described in Example 87, except using as starting material, the title compound was obtained in 55% yield as a white solid.

Hydrochloride: The results of elemental analyzes for the dihydrochloride did not agree with the theory. The 1 H NMR and MS results of the hydrochloride were completely consistent.

The starting material amide was prepared as follows.

a. Methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate

Methyl 2-amino-7-chloro-9,10-dihydro-9 in methylene chloride (5 mL) under nitrogen in boron trifluoride etherate (0.413 mL, 3.36 mmol, 1.5 equiv) cooled to -15 ° C. A solution of 10-methano-9-anthracenecarboxylate (as described in Example 35c) was added. This was followed by the addition of t-butyl nitride (0.320 mL, 2.69 mmol, 1.2 equiv), which formed a precipitate and the solution turned dark blue green. After 10 minutes at −15 ° C., the reaction was warmed to 0 ° C. and then further stirred for 20 minutes. Dilution with pentane (100 mL) charged the diazonium salt. The precipitate was filtered off and washed with cold diethyl ether to recover 650 mg of crude salt. At 0 ° C., diazonium salt was added to a solution of potassium carbonate (155 mg, 0.5 equiv) in trifluoroacetic acid (5 mL). The reaction was refluxed for 20 hours, with basic β-naphthol test results for diazonium salts negative. Water (5 mL) was added to terminate the reaction, and trifluoroacetic acid was removed in vacuo. The crude reaction mixture was diluted with 3N HCl (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography on silica gel (35 mL, eluent: 10% ethyl acetate in hexanes) to give 540 mg (80%) of the title compound as a white solid.

TLC analysis (R _f 0.21, 10% ethyl acetate in hexanes).

MS (CI, CH4) m / z 301 (M + 1, 100), 303 (42), 329 (M + 29, 10), 269 (31), 241 (56)

b. 2-Chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

Except that methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in Example 90a) is used as starting material. Using a method similar to that described in Example 35e, the title compound was obtained in 87% yield as a white solid. Subsequent reactions were performed without further characterization.

c. 1- (2-chloro-7-hydroxy-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol

Example, except using 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 90b) as starting material Using a method similar to that described in 87a, the title compound was obtained in 37% yield as off-white foam.

TLC analysis (R _f 0.18, 5% methanol in ether.)

MS (CI, CH4) m / z 447 (M + 1, 100), 449 (38), 475 (M + 29, 25), 429 (35)

Example 91

1- (2-Chloro-7-methoxy-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol

1- (2-chloro-7-methoxy-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol Using the method analogous to that described in Example 87, except using as starting material, the title compound was obtained in 68% yield as a white solid.

The starting material amide was prepared as follows.

a. Methyl 2-chloro-7-methoxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate

Potassium carbonate and methyl iodide were added to an ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (as described in Example 90a). Added. The suspension was heated to reflux and cooled, then diluted with diethyl ether, filtered to remove salts and then concentrated to give a solid. The title compound was obtained in 90% yield.

TLC analysis (R _f 0.40, 20% ethyl acetate in hexanes).

MS (CI, CH4) m / z 315 (M + 1, 100), 343 (M + 29, 13), 301 (38), 287 (9), 279 (14), 265 (6), 255 (42 ).

b. 2-Chloro-7-methoxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid

Example, except using 2-chloro-7-methoxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in Example 91a) as starting material Using the method similar to that described in 35e, the title compound was obtained in quantitative yield. The subsequent reaction was carried out without further purification.

c. 1- (2-chloro-7-methoxy-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol and 1- (2,6-dichloro-7-methoxy-9,10-dihydro-9,10-methanoanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidine-4- Toluene solution of all 2-chloro-7-methoxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (as described in Example 91b) (1.15 g, 3.82 mmol) (10 thionyl chloride (0.56 mL, 7.6 mmol, 2 equiv) was added to the mL). Gas foaming was monitored by the mineral oil foaming device while the reaction was heated to reflux for 1 hour. Toluene was removed and replaced with clean toluene and stripped to dryness. This procedure was repeated twice. The residue was dissolved in tetrahydrofuran (10 mL). To this solution was added triethylamine (0.53 mL, 3.8 mmol, 1 equiv) and 4-hydroxy-4- (3-pyridyl) piperidine (Example 87e) (0.75 g, 4.2 mmol, 1.1 equiv) It was. The tetrahydrofuran solution was heated to reflux for 18 hours, cooled to room temperature and poured into diethyl ether (100 mL). The organic phase was washed with 2.5N NaOH (3 × 25 mL) and saturated brine, dried over magnesium sulfate, filtered and concentrated to give an oil. The reaction product was purified by flash chromatography on silica gel (60 mL, eluent: ethyl acetate) to give 1.00 g of a white solid.

TLC analysis (R _f 0.20, ethyl acetate).

A solid consisting of an inseparable mixture of the desired amide (23% total) and 2,6-dichloro-7-methoxymethanoanthracene amide (36% total) was obtained. The mixture was no longer characterized because the concentrated product was separable by flash chromatography.

Example 92

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylsulfinyl-3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylthio-3-pyridyl) piperidine- in acetic acid / water (22 mL / 5 mL) To a cooled (0 ° C.) solution of 4-ol (Example 60) (0.500 g, 1.13 mmol) was added dropwise potassium permanganate (0.179 g, 1.13 mmol, 1.0 equiv) based on manganese (8 mL of water). TLC or HPLC (reverse phase methanol / water, C18 column) was used to monitor whether excessive oxidation of the substrate to sulfone was seen. After addition of 6 mL of the oxidation reaction solution, sulfone began to form. The oxidation reaction was completed almost immediately. The reaction was terminated with a saturated aqueous sodium bisulfite solution (50 mL) and basified with an aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by flash chromatography on silica gel (60 mL, eluent: 15% methanol / ethyl acetate) to give 260 mg (50%) of the title compound as a white solid. The nonpolar component of the chromatography was purified again using fresh silica gel (60 mL, eluent: 80% diethyl ether / hexane) to separate 170 mg (37%) of the corresponding sulfone (Example 98). TLC analysis (sulfoxide: Rf 0.24, sulfone Rf 0.73, eluent: 15% methanol / ethyl acetate). Both free bases were dissolved in methylene chloride, acidified with etheric HCl and diluted with ether. The hydrochloride formed was filtered, washed with clean ether and dried in vacuo (55 ° C., 10 Pascal, 18 h) to give a white solid. mp sulfoxide 214-216 ° C. (decomposed). Sulfone 225-228 ° C. (decomposed).

Example 93

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylpopinyl-3-pyridyl) piperidin-4-ol

Using the same method as described in Example 97, the title compound was isolated in hydrochloride form.

Example 94

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) piperidin-4-ol

Except for using 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidone (described in Example 1m) as starting material Using the method analogous to that described in Example 58, the title compound was obtained in 64% yield as a white solid.

Example 95

1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylthio-3-pyridyl) piperidin-4-ol

1- (2-Chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) piperidin-4-ol (implemented Using the method analogous to that described in Example 60, except that Example 99) was used as the starting material, the title compound was obtained in 93% yield as a white solid.

Example 96

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (1,1-dimethylethylsulthio-3-pyridyl) piperidine-4- Come

Using the method analogous to that described in Example 60, except using t-butylthiol as starting material, the title compound was obtained as a citrate in 70% yield.

Example 97

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-methylthio-3-pyridyl) piperidin-4-ol

Using the same method as described in Example 60, except for using methyl thiol as starting material, the title compound was obtained in 63% yield as white hydrochloride.

Example 98

1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2- (2-N, N-dimethylaminoethylthio) -3-pyridyl) piperidine -4-ol

Using the method analogous to that described in Example 60, except using 2-dimethylaminoethanethiol as starting material, the title compound was obtained in 58% yield as white hydrochloride.

Example 99

4- (2- (4-acetamidophenylthio) -3-pyridyl-1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) piperidin-4-ol

Using the method similar to that described in Example 60, except using 4-acetamidothiophenol as the starting material, the title compound was obtained as a white hydrochloride in 26% yield.

Example 100

1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (1,1-dimethylethyl) piperidine-4- Come

1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4-piperidinone (Example 1m, Optics described in Example 1n Using the method analogous to that described in Example 49, except using an active acid formulation) as the starting material, the title compound was obtained in 29% yield as a white hydrochloride.

Example 101

1- (9,10-dihydro-9,10-methano-2-methoxyanthracene-9-ylmethyl) -4- (3-pyridyl) piperidin-4-ol

1- (9,10-dihydro-9,10-methano-2-methoxyanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol (described below) ) The title compound was obtained in 66% yield as white hydrochloride using a method similar to that described in Example 87 except for using) as the starting material.

The starting material amide was prepared as follows.

a. 9,10-dihydro-9,10-methano-2-methoxyanthracenecarboxylic acid

Example 88, except that 2-chloro-9,10-dihydro-9,10-methano-7-methoxy-anthracenecarboxylic acid (as described in Example 91b) is used as starting material. Using a method similar to that described, the title compound was obtained in 65% yield as a white solid. The product was characterized by mass spectra only.

MS (CI, CH 4) m / z 267 (M + l, 100), 284 (M + 29, 50), 249 (9), 221 (11).

b. 1- (9,10-dihydro-9,10-methano-2-methoxyanthracene-9-ylcarbonyl) -4- (3-pyridyl) piperidin-4-ol

Using a method similar to that described in Example 87a, except using 9,10-dihydro-9,10-methano-2-methoxyanthracene carboxylic acid (Example 101a) as starting material, The title compound was obtained in 23% yield as an oil.

Example 102

As described below, a pharmaceutical dosage form containing a compound of Formula (I) (hereinafter referred to as "Compound X"), eg, any of those described in the above-described examples, may be used for the treatment of human or Useful for disease prevention

The formulations can be obtained by conventional methods known in the pharmaceutical art. The tablets may be coated by conventional means, for example with cellulose acetate phthalate.

Claims (9)

Compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: Wherein X and Y are each selected from hydrogen, halo and (1-6C) alkoxy and R^OneSilver (A) (1-6C) alkyl, (B) (1-6C) alkyl, (1-6C) alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl , General formula SO₂NR^aR^bAminosulfonyl represented by^cR^dAminocarbonyl represented by^a, R^b, R^cAnd R^dAre each selected from hydrogen, 2-pyrrolidinyl and (1-6C) alkyl, or R^aAnd R^b, And R^cAnd R^dend Together with the nitrogen atom to which they are each bonded form a 5- or 6-membered heterocyclic ring in which said nitrogen atom is the only hetero atom) and R^hRⁱN (1-3C) alkyl, where R^hAnd RⁱIs phenyl and naphthyl which may each have 0-3 substituents selected from the group consisting of hydrogen and (1-3C) alkyl, (C) phenyl (1-3C) alkyl and naphthyl (1-3C) Alkyl (where phenyl and naphthyl groups may have 0 to 3 substituents selected from the phenyl and naphthyl substituents described in (B) above), (D) 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (1-6C) alkoxy, (1-6C) alkoxycarbonyl, (1-6C) hydroxyalkyl, benzyloxy, halo which may contain (1-6C) alkyl, hydroxy, trifluoromethyl groups , (1-3C) alkylaminocarbonyl (1-3C) alkyl, aminocarbonyl as described in (B) above, R^eS (0)_n, R^fNH and R^g5- and 6-membered heteroaryl rings, or benz derivatives thereof, which may have 0 to 2 substituents selected from S, wherein R^eAnd R^fAre each selected from hydrogen and (1-6C) alkyl, n is 0, 1 or 2, and R is^gIs selected from (1-3C) alkylcarbonylaminophenyl and di (1-3C) alkylamino (1-6C) alkyl), and (E) a 5 or 6 membered heteroaryl moiety as described in (D) above It is selected from the heteroaryl (1-3C) alkyl which is a circular ring and may have 0-2 substituents chosen from the meaning of the heteroaryl substituent as described in said (D). The compound of claim 1, wherein X and Y are each selected from hydrogen and halo. The compound of claim 2, wherein X and Y are each selected from hydrogen and chloro, and R ¹ is (i) t-butyl, (ii) 2-methoxyphenyl, 3-methoxyphenyl and the general formula R ^a R ^b NSO Phenyl substituted at the 2- or 3-position by aminosulfonyl represented by ₂ (wherein R ^a and R ^b are each selected from hydrogen, methyl and ethyl), (iii) thienyl, furyl and 2-position (1 -6C) alkoxy, (1-6C) alkylthio or (1-6C) alkylsulfinyl. 3-Pyridyl optionally substituted with a compound. 4. The compound of claim 3, wherein 1-((9S, 10S) -2-chloro-9,10-dihydro-9,10-methanoanthracene-9-yl-methyl) -4- (1,1-dimethylethyl Piperidin-4-ol, 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylsulfinyl-3-pyridyl) piperidine -4-ol, 1- (9,10-dihydro-9,10-methanoanthracene-9-ylmethyl) -4- (2-ethylthio-3-parisilyl) piperidin-4-ol and In 1- (2-chloro-9,10-dihydro-9,10-methanoanthracene-9-yl-methyl) -4- (2-methoxy-3-pyridyl) piperidin-4-ol The compound selected. A pharmaceutical composition for treating a neuropsychiatric disorder, comprising a compound represented by formula (I) according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient or carrier. Compound represented by the following general formula (II): Wherein X and Y are each selected from hydrogen, halo and (1-6C) alkoxy. Compound represented by the following general formula (IIa): Wherein X, Y and R ¹ are as defined in claim 1. Compound represented by the following general formula (III): Wherein X and Y are each selected from hydrogen, halo and (1-6C) alkoxy and G is selected from chloro, OH and H, except for compounds in which both X and Y are H when G is H or OH do. (a) the piperidone represented by the following general formula (II) is treated with the corresponding compound represented by the general formula R ¹ Li in an aprotic solvent, or (b) the corresponding amide represented by the following general formula (IIa) Is treated with a suitable reducing agent or (c) the aldehyde represented by the following general formula (III) (wherein G is a hydrogen atom) with the corresponding piperidine represented by the following general formula (IV) in the presence of a reducing agent Or (d) to prepare a compound represented by formula (I) wherein either X or Y is (1-6C) alkoxy, the corresponding formula of formula (I) wherein X or Y is hydroxy The compound is treated with the corresponding (1-6C) ylalkyl halide in the presence of a base, and then, if a pharmaceutically acceptable salt is to be prepared, the compound is reacted in a conventional manner with a suitable acid. Unity represented by the following general formula (I) Or a process for preparing a pharmaceutically acceptable salt of this: Wherein X, Y and R ¹ are as defined in claim 1.